Receptor-Type Kinase Modulators and Methods of Use

ABSTRACT

The present invention provides compounds for modulating receptor kinase activity, particularly ephrin and EGFR, and methods of treating diseases mediated by receptor kinase activity utilizing the compounds and pharmaceutical compositions thereof. Diseases mediated by receptor kinase activity include, but are not limited to, diseases characterized in part by abnormal levels of cell proliferation (i.e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth. Compounds of the invention include “spectrum selective” kinase modulators, compounds that inhibit, regulate and/or modulate signal transduction across subfamilies of receptor-type tyrosine kinases, including ephrin and EGFR.

CROSS-REFERENCE

This application is a continuation of prior, copending application Ser.No. 12/455,867, filed on Jun. 8, 2009, which is a continuation of prior,copending application Ser. No. 10/522,004, filed on Apr. 11, 2005, nowU.S. Pat. No. 7,576,074, issued on Aug. 18, 2009, which is a nationalphase application of PCT Application No. PCT/US03/21923, filed on Jul.14, 2003, which claims the benefit of U.S. Provisional Application No.60/396,269, filed on Jul. 15, 2002, and 60/447,212, filed on Feb. 13,2003. The contents of the prior applications are hereby incorporated byreference in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to compounds for modulating protein kinaseenzymatic activity for modulating cellular activities such asproliferation, differentiation, programmed cell death, migration andchemoinvasion. Even more specifically, the invention relates toquinazolines which inhibit, regulate and/or modulate kinase receptorsignal transduction pathways related to the changes in cellularactivities as mentioned above, compositions which contain thesecompounds, and methods of using them to treat kinase-dependent diseasesand conditions.

SUMMARY OF RELATED ART

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation ofproteins, in particular, hydroxy groups on tyrosine, serine andthreonine residues of proteins. The consequences of this seeminglysimple activity are staggering; cell differentiation and proliferation;i.e., virtually all aspects of cell life in one-way or another depend onprotein kinase activity. Furthermore, abnormal protein kinase activityhas been related to a host of disorders, ranging from relativelynon-life threatening diseases such as psoriasis to extremely virulentdiseases such as glioblastoma (brain cancer).

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases have an extracellular, atransmembrane, and an intracellular domain, while non-receptor typetyrosine kinases are wholly intracellular.

Receptor-type tyrosine kinases are comprised of a large number oftransnmernbrane receptors with diverse biological activity. In fact,about twenty different subfamilies of receptor-type tyrosine kinaseshave been identified. One tyrosine kinase subfamily, designated the HERsubfamily, is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands ofthis subfamily of receptors identified so far include epithelial growthfactor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.Another subfamily of these receptor-type tyrosine kinases is the insulinsubfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamilyincludes the PDGF-alpha and beta-receptors, CSFIR, c-kit and FLK-II.Additionally there is the FLK family, which is comprised of the kinaseinsert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liverkinase-4 (FLK-4) and the fins-like tyrosine kinase-1 (flt-1). The PDGFand FLK families are usually considered together due to the similaritiesof the two groups. For a detailed discussion of the receptor-typetyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994, which ishereby incorporated by reference for all purposes.

The non-receptor type of tyrosine kinases is also comprised of numeroussubfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak,Jak, Ack, and LIMK. Each of these subfamilies is further sub-dividedinto varying receptors. For example, the Src subfamily is one of thelargest and includes Src, Yes, Fyn, Lyn, Lck, Blk, H-Ick, Fgr, and Yrk.The Src subfamily of enzymes has been linked to oncogenesis. For a moredetailed discussion of the non-receptor type of tyrosine kinases, seeBolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated byreference for all purposes.

Since protein kinases anid their ligands play critical roles in variouscellular activities, deregulation of protein kinase enzymatic activitycan lead to altered cellular properties, such as uncontrolled cellgrowth associated with cancer. In addition to oncological indications,altered kinase signaling is implicated in numerous other pathologicaldiseases. These include, but are not limited to: immunologicaldisorders, cardiovascular diseases, inflammatory diseases, anddegenerative diseases. Therefore, both receptor and non-receptor proteinkinases are attractive targets for small molecule drug discovery.

One particularly attractive goal for therapeutic use of kinasemodulation relates to oncological indications. For example, modulationof protein kinase activity for the treatment of cancer has beendemonstrated successfully with the FDA approval of Gleevec® (imatinibmesylate, produced by Novartis Pharmaceutical Corporation of EastHanover, N.J.) for the treatment of Chronic Myeloid Leukemia (CML) andgastrointestinal stroma cancers (GIST). Gleevec is a c-Kit and Ablkinase inhibitor.

Modulation (particularly inhibition) of cell proliferation andangiogenesis, two key cellular processes needed for tumor growth andsurvival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is anattractive goal for development of small-molecule drugs. Anti-angiogenictherapy represents a potentially important approach for the treatment ofsolid tumors and other diseases associated with dysregulatedvascularization, including ischemic coronary artery disease, diabeticretinopathy, psoriasis and rheumatoid arthritis. As well, cellantiproliferative agents are desirable to slow or stop the growth oftumors.

Inhibition of EGF, VEGF and ephrin signal transduction will prevent cellproliferation and angiogenesis, two key cellular processes needed fortumor growth and survival (Matter A. Drug Disc Technol 2001 6,1005-1024). VEGF receptors are previously described targets for smallmolecule inhibition.

The Eph receptors comprise the largest family of receptor tyrosinekinases and are divided into two groups, EphA and EphB, based on theirsequence homology. The ligands for the Eph receptors are ephrin, whichare membrane anchored. Ephrin A ligands bind preferentially to EphAreceptors whilst ephrin B ligands bind to EphB receptors. Binding ofephrin to Eph receptors causes receptor autophosphorylation andtypically requires a cell-cell interaction since both receptor andligand are membrane bound.

Overexpression of Eph receptors has been linked to increased cellproliferation in a variety of tumors (Zhou R 1998 Pharmacol Ther. 77,151-181; Kiyokawa E, Takai S, Tanaka M et al 1994 Cancer Res 54,3645-3650; Takai N Miyazaki T, Fujisawa K, Nasu K and Miyakawa. 2001Oncology reports 8, 567-573). The family of Eph receptor tyrosinekinases and their ephrin ligands play important roles in a variety ofprocesses during embryonic development and also in pathologicalangiogenesis and potentially metastasis. Therefore modulation of Ephreceptor kinase activity should provide means to treat or preventdisease states associated with abnormal cell proliferation such as thosedescribed above.

The epidermal growth factor receptor (EGFR, HER1, erbB1) is part of afamily of plasmam membrane receptor tyrosine kinases that controlcellular growth, proliferation and apoptosis. The ligand for EGFR is theepidermal growth factor and dysregulation of the EGFR signaltransduction pathway has been implicated in tunorigenesis and cancerprogression thus making it a clinically relevant target for novelanticancer treatments Drevs J et al 2003 Curr Drug Targets 4, 113-121;Ciardiello F and Tortora G. 2001 Clin. Cancer Res. 7, 2958-2970; ThomasM. 2002 Semin Onc. Nurs 18, 20-27).

EGFR is overexpressed in different human cancers especially non-smallcell lung cancer and glioblastomas. In these cancers, EGFRoverexpression is commonly associated with advanced disease and poorprognosis (Baselga J et al 1999 Semin. Oncol. 26, 78-83).

Accordingly, the identification of small-molecule compounds thatspecifically inhibit, regulate and/or modulate the signal transductionof tyrosine kinases, particularly ephrin and EGFR receptor kinases, isdesirable as a means to treat or prevent disease states associated withabnormal cell proliferation and is an object of this invention.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds for modulatingkinase activity, particularly ephrin receptor kinase (from hereindenoted “ephrin”) activity and/or EGFR activity; methods of treatingdiseases mediated by such activity utilizing the compounds andpharmaceutical compositions thereof. Diseases mediated by ephrininclude, but are not limited to, diseases characterized in part byabnormal cell migration and invasion and angiogenesis associated withtumor growth. Diseases mediated by EGF driven signal transductioninclude, but are not limited to, diseases characterized by abnormallevels of cell proliferation (i.e. tumor growth) and programmed celldeath (apoptosis). Diseases mediated by both ephrin and EGF includediseases characterized by both abnormal cell proliferation andangiogenesis which are associated with tumor growth.

Inhibitors that are selective for a particular kinase, for exampleephrin and EGFR, are included in this invention. However, another aspectof the invention are compounds that inhibit, regulate and/or modulatethe signal transduction receptor tyrosine kinase families, familymembers, or otherwise related sets of kinases. Such related kinasefamilies may include receptor-type tyrosine kinases of the HER, FLK andinsulin subfamilies, which demonstrate similarity in both structure andbroad biochemical function. Thus quinazolines of the invention include“spectrum selective” kinase modulators. “Spectrum selective” kinasemodulators are defined as quinazolines of the invention that inhibit,regulate and/or modulate signal transduction across various subfamiliesof receptor-type tyrosine kinases including those of ephrin and EGFRreceptor tyrosine kinase subfamilies.

In another aspect, the invention provides methods of screening formodulators of receptor tyrosine kinase activity, for example activity ofephrin and EGFR. The methods comprise combining a composition of theinvention, a receptor tyrosine kinase, and at least one candidate agentand determining the effect of the candidate agent on the kinaseactivity.

In yet another aspect, the invention also provides pharmaceutical kitscomprising one or more containers filled with one or more of theingredients of pharmaceutical compounds and/or compositions of thepresent invention, including, one or more tyrosine receptor kinaseactivity modulators as described herein. Such kits can also include, forexample, other compounds and/or compositions (for example, diluents,permeation enhancers, lubricants, and the like), a device(s) foradministering the compounds and/or compositions, and writteninstructions in a form prescribed by a governmental agency regulatingthe manufacture, use or sale of pharmaceuticals or biological products,which instructions can also reflects approval by the agency ofmanufacture, use or sale for human administration.

In still yet another aspect, the invention also provides a diagnosticagent comprising a compound of the invention and, optionally,pharmaceutically acceptable adjuvants and excipients.

These and other features and advantages of the present invention will bedescribed in more detail below with reference to the associateddrawings.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of the invention are used to treat diseases associatedwith abnormal and or unregulated cellular activities. Disease stateswhich can be treated by the methods and compositions provided hereininclude, but are not limited to, cancer (further discussed below),immunological disorders such as rheumatoid arthritis, graft-hostdiseases, multiple sclerosis, psoriasis; cardiovascular diseases such asartheroscrosis, myocardioinfarction, ischemia, stroke and restenosis;other inflammatory and degenerative diseases such as interboweldiseases, osteoarthritus, macular degeneration, diabetic retinopathy.

It is appreciated that in some cases the cells may not be in a hyper- orhypo-proliferative and/or migratory state (abnormal state) and stillrequire treatment. For example, during wound healing, the cells may beproliferating “normally”, but proliferation and migration enhancementmay be desired. Alternatively, reduction in “normal” cell proliferationand/or migration rate may be desired.

The present invention comprises a compound for modulating tyrosinekinase activity of Formula I,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereofwherein,

-   -   R¹ is C₁-C₃ alkyl optionally substituted with between one and        three R⁵⁰ substituents;    -   R² is selected from —H, halogen, trihalomethyl, —CN, —NH₂, —NO₂,        —OR³, —N(R³)R⁴, —S(O)₀₋₂R⁴, —SO₂N(R³)R⁴, —CO₂R³, —C(═O)N(R³)R⁴,        —N(R³)SO₂R⁴, —N(R)C(═O)R³, —N(R³)CO₂R⁴, —C(═O)R³, optionally        substituted lower alkyl, optionally substituted lower alkenyl,        and optionally substituted lower alkynyl;    -   R³ is —H or R⁴;    -   R⁴ is selected from optionally substituted lower alkyl,        optionally substituted aryl, optionally substituted lower        arylalkyl, optionally substituted heterocyclyl, and optionally        substituted lower heterocyclylalkyl; or    -   R³ and R⁴, when taken together with a common nitrogen to which        they are attached, form an optionally substituted five- to        seven-membered heterocyclyl, said optionally substituted five-        to seven-membered heterocyclyl optionally containing at least        one additional heteroatom selected from N, O, S, and P;    -   q is zero to five;    -   Z is selected from —OCH₂—, —O—, —S(O)₀₋₂—, —N(R⁵)CH₂—, and        —NR⁵—;    -   R⁵ is —H or optionally substituted lower alkyl;    -   M¹ is —H, C₁-C₈ alkyl-L²-L¹-optionally substituted by R⁵⁰,        G(CH₂)₀₋₃—, or R⁵³(R⁵⁴)N(CH₂)₀₋₃—; wherein G is a saturated        five- to seven-membered heterocyclyl containing one or two        annular heteroatoms and optionally substituted with between one        and three R₅₀ substituents; L¹ is —C═O— or —SO₂—; L² is a direct        bond, —O—, or —NH—; and R⁵³ and R are independently C₁-C₃ alkyl        optionally substituted with between one and three R⁵⁰        substituents;    -   M² is a saturated or mono- or poly-unsaturated C₃-C₁₄ mono- or        fused-polycyclic hydrocarbyl optionally containing one, two, or        three annular heteroatoms per ring and optionally substituted        with between zero and four R⁵⁰ substituents; and    -   M³ is —NR⁹—, —O—, or absent;    -   M⁴ is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or absent;    -   R⁹ is —H or optionally substituted lower alkyl;    -   R⁵⁰ is —H, halo, trihalomethyl, —OR³, —N(R³)R⁴, —S(O)₀₋₂R,        —SO₂N(R³)R⁴, —CO₂R³, —C(═O)N(R³)R⁴, —C(═NR²⁵)N(R³)R⁴,        —C(═NR²⁵)R⁴, —N(R³)SO₂R⁴, —N(R³)C(O)R³, —NCO₂R³, —C(═O)R³,        optionally substituted alkoxy, optionally substituted lower        alkyl, optionally substituted aryl, optionally substituted lower        arylalkyl, optionally substituted heterocyclyl, and optionally        substituted lower heterocyclylalkyl; or    -   two of R⁵⁰, when taken together on the same carbon are oxo; or    -   two of R⁵⁰, when taken together with a common carbon to which        they are attached, form a optionally substituted three- to        seven-membered spirocyclyl, said optionally substituted three-        to seven-membered spirocyclyl optionally containing at least one        additional heteroatom selected from N, O, S, and P; and    -   R²⁵ is selected from —H, —CN, —NO₂, —OR³, —S(O)₀₋₂R⁴, —CO₂R³,        optionally substituted lower alkyl, optionally substituted lower        alkenyl, and optionally substituted lower alkynyl.

Embodiment [0025]

In one example, the compound is according to Formula I, wherein M⁴ is—CH₂—.

Embodiment [0026]

In another example, the compound is according to Embodiment [0025],wherein Z is —NR—.

Embodiment [0027]

In another example, the compound is according to Embodiment [0026],wherein R¹ is CH₃—.

Embodiment [0028]

In another example, the compound is according to Embodiment [0027],wherein

of I is selected from:

wherein R^(2a) is selected from —H, F, Cl, and Br; and R^(2b) and R^(2c)are each independently selected from F, Cl, and Br.

Embodiment [0029]

In one example, the compound is according to Embodiment [0028], whereinM² is a monocyclic five- to seven-membered heterocyclyl or a five- tosix-membered heteroaryl, each optionally substituted with between oneand three of R⁵⁰.

Embodiment [0030]

In another example, the compound is according to Embodiment [0029],wherein M² is selected from the group consisting of morpholinyl,thiazolyl, oxadiazolyl, tetrahydropyranyl, and oxazepanyl, eachoptionally substituted with between one and three of R⁵⁰.

Embodiment [0031]

In another example, the compound is according to Embodiment [0030],wherein M¹ is selected from the group consisting of —H,dimethylaminomethyl, (4-methylpiperazin-1-yl)methyl, piperidinyl,1-methylpiperidin-4-yl, morpholin-4-ylmethyl, and phenylmethyl.

Embodiment [0032]

In another example, the compound is according to Embodiment [0031],wherein

of I is

Embodiment [0033]

In another example, the compound is according to Embodiment [0028],wherein M¹ is either a three- to seven-membered saturated carbocyclyl ora heterocyclyl with one or two annular heteroatoms, wherein the eitherof the aforementioned are optionally substituted with at least one ofC₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, R¹⁰(R¹¹)N—, and hydroxy,provided there are no gemninal heteroatom substitutions; and wherein R¹⁰and R¹¹ are each independently C₁-C₃ alkyl.

Embodiment [0034]

In another example, the compound is according to Embodiment [0033],wherein

of I is

Embodiment [0035]

In another example, the compound is according to Embodiment [0024],wherein M¹-M²-M³-M⁴-together are according to formula II;

-   -   wherein X¹, X², and optionally X³, represent the atoms of a        saturated bridged ring system, said saturated bridged ring        system containing up to three annular heteroatoms represented by        any of X¹, X², and X³; wherein,    -   each X¹ is independently selected from —C(R⁶)R⁷—, —O—,        —S(O)₀₋₂—, and —NR⁸—;    -   each X² is independently a bridgehead minethine optionally        substituted with R⁶, or a bridgehead nitrogen;    -   each X³ is independently selected from —C(R⁶)R⁷—, —O—,        —S(O)₀₋₂—, and —NR⁸—;    -   provided, for X¹, X², and X³, there are no nitrogen-nitrogen        annular bonds nor geminal di-nitrogen substitutions;    -   E is selected from —NR⁹—, —O—, and absent;    -   Y is either:        -   a C₁₋₃ alkylene linker, between the oxygen at the 7-position            of the quinazoline ring system of I and either E, or when E            is absent, any ring atom of the saturated bridged ring            system except X², when X² is a bridgehead nitrogen, provided            there are at least two carbon atoms between the oxygen at            the 7-position of the quinazoline ring system of I and            either E, or when E is absent, any heteroatom represented by            X¹, X² or X³; or        -   Y is absent, when Y is absent, E is also absent; said            saturated bridged ring system is directly attached to the            oxygen at the 7-position of the quinazoline ring system of I            via a carbon atom of said saturated bridged ring system;    -   m and p are each independently between one and four;    -   n is between zero and two, when n is zero, then there is a        direct single bond between the two bridgehead X²'s;    -   R⁶ and R⁷ are each independently selected from —H, halogen,        trihalomethyl, —CN, —NH₂, —NO₂, —OR³, —N(R³)R⁴, —S(O)₀₋₂R⁴,        —SO₂N(R³)R⁴, —CO₂R³. —C(O)N(R)R⁴, —N(R³)SO₂R⁴, —N(R³)C(O)R³,        —NCO₂R³, —C(O)R³, optionally substituted lower alkyl, optionally        substituted aryl, optionally substituted lower arylalkyl,        optionally substituted heterocyclyl, optionally substituted        lower heterocyclylalkyl; or    -   R⁶ and R⁷, when taken together are oxo; or    -   R⁶ and R⁷, when taken together with a common carbon to which        they are attached, form a optionally substituted three- to        seven-membered spirocyclyl, said optionally substituted three-        to seven-membered spirocyclyl optionally containing at least one        additional heteroatom selected from N, O, S, and P; and    -   R⁸ is selected from R³, —SO₂N(R³)R⁴, —CO₂R³, —C(O)N(R³)R⁴,        —SO₂R⁴ and —C(O)R³,    -   with the proviso that when Y is a C₁₋₃ alkylene linker; E is        absent, Z is —NH— or —N(CH₃)—; R¹ is a C₁₋₃ alkyl; R² is —H or        halogen; n=0; and, the atoms, X¹, of one bridge of the saturated        bridged ring system, when combined with both bridgehead atoms,        X², of the saturated bridged ring system, represent:        -   either a pyrrolidine ring or a piperidine ring, and any            atom, X¹ or X², of either of said pyrrolidine ring or said            piperidine ring is attached to Y, then the other bridge of            said saturated bridged ring system cannot be any one of            —OC(O)CH₂—, —CH₂OC(O)—, —OC(O)CH₂CH₂—, —CH₂OC(O)CH₂—,            —CH₂CH₂OC(O)—, —OC(O)CH₂NH—, —OC(O)CH₂N(C₁₋₄alkyl)-, and            —OC(O)CH₂O—; or        -   either a piperazine ring or a 4-(C₁₋₄ alkyl)-piperazine            ring, and any atom, X¹ or X², of either of said piperazine            ring or said 4-(C₁₋₄ alkyl)-piperazine ring is attached to            Y, then the other bridge of said saturated bridged ring            system, only when attached via the 2- and the 3-position of            either of said piperazine ring or said 4-(C₁₋₄            alkyl)-piperazine ring, cannot be one of —CH₂OC(O)CH₂—,            —CH₂CH₂C(O)—, and either of the two aforementioned bridges            optionally substituted by one or two C₁₋₂alkyl groups; or    -   a piperazine ring, and any atom, X¹ or X², of said piperazine        ring is attached to Y, then the other bridge of said saturated        bridged ring system, only when attached via the 3- and the        4-position of said piperazine ring, cannot be one of        —C(O)OCH₂CH₂—, —CH₂OC(O)CH₂—, and either of the two        aforementioned bridges optionally substituted by one or two C₁₋₂        alkyl groups, and only when either of the two aforementioned        bridges are attached to the 3-position of said piperazine ring        via their left-hand end as depicted above; or    -   a 2-oxomorpholine ring, said 2-oxomorpholine ring attached to Y        via its 4-position, then the other bridge of said saturated        bridged ring system, only when attached via the 5- and the        6-position of said 2-oxomorpholine ring, cannot be one of        —(CH₂)_(g)—, —CH₂WCH₂—, —CH₂WCH₂CH₂—, and —CH₂CH₂WCH₂—, wherein        W is —O—, —S(O)₀₋₂—, —NH—, or —N(C₁₋₄ alkyl)-wherein g is 2, 3,        or 4.

Embodiment [0036]

In one example, the compound is according to Embodiment [0035], whereinZ is —NR⁵—.

Embodiment [0037]

In another example, the compound is according to Embodiment [0036],wherein R² is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —OR³,and optionally substituted lower alkyl.

Embodiment [0038]

In another example, the compound is according to Embodiment [0037],wherein R¹ is an unsubstituted C₁₋₃ alkyl.

Embodiment [0039]

In another example, the compound is according to Embodiment [0038],wherein the saturated bridged ring system has a geometry selected fromthe group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0],[3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2],and [2.2.1].

Embodiment [0040]

In another example, the compound is according to Embodiment [0039],wherein Y is selected from —CH₂CH₂—, —CH₂—, and absent.

Embodiment [0041]

In another example, the compound is according to Embodiment [0040],wherein q is one, two, or three.

Embodiment [0042]

In another example, the compound is according to Embodiment [0041],wherein R⁵ is —H.

Embodiment [0043]

In another example, the compound is according to Embodiment [0042],wherein R¹ is methyl.

Embodiment [0044]

In another example, the compound is according to Embodiment [0043],wherein the saturated bridged ring system has a geometry selected fromthe group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0],[3.2.0], and [3.1.0].

Embodiment [0045]

In another example, the compound is according to Embodiment [0044],wherein said saturated bridged ring system contains one or two annularnitrogens, said one or two annular nitrogens are selected from —NR⁸—,when X¹, and a bridgehead nitrogen, when X².

Embodiment [0046]

In another example, the compound is according to Embodiment [0045],wherein E is absent.

Embodiment [0047]

In another example, the compound is according to Embodiment [0046],wherein said saturated bridged ring system is according to formula III;

wherein A is selected from —O—, —S(O)₀₋₂—, —NR⁸—, and absent; and e is 0or 1.

Embodiment [0048]

In another example, the compound is according to Embodiment [0047],wherein Y is —CH₂—.

Embodiment [0049]

In another example, the compound is according to Embodiment [0048],wherein A is selected from —NR⁸—, wherein R⁸ is selected from —H,optionally substituted lower alkyl, —CO₂R³, —C(O)N(R³)R⁴, —SO₂R³, and—C(O)R³; —O—; and absent.

Embodiment [0050]

In another example, the compound is according to Embodiment [0049],wherein

of I is selected from:

and wherein R^(2a), R^(2b), and R^(2c) are each independently selectedfrom F, Cl, and Br.

Embodiment [0051]

In another example, the compound is according to Embodiment [0050],wherein R^(2a) is F, R^(2b) is Cl, and R^(2c) is either Cl or Br.

Embodiment [0052]

In another example, the compound is according to Formula Ia;

-   -   or a pharmaceutically acceptable salt or hydrate thereof,        wherein    -   q is 1, 2, or 3;    -   R² is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —OR³,        and optionally substituted lower alkyl;    -   E is selected from —NR⁹—, —O—, and absent;    -   Y is selected from —CH₂CH₂—, —CH₂—, and absent;    -   wherein R¹⁰ is selected from —H optionally substituted alkyl,        and —OR³; and R¹¹ and R¹² are each independently selected from        —H, —CF₃, —F, —N(R³)R⁴, —N(C═O)R³, —N(R³)SO₂R³, —S(O)₀₋₂R¹³, and        —OR¹³; or    -   R¹¹ is selected from —H, and —OR¹³; and    -   R¹¹ and R¹², when taken together, are oxo, exo-alkenyl, or when        taken together with the carbon to which they are attached, form        a three- to seven-membered spirocyclyl;    -   R¹³ is selected from —H, —C(═O)R⁴, optionally substituted lower        alkynlyl, optionally substituted lower arylalkynyl, optionally        substituted lower heterocyclylalkynyl, optionally substituted        lower alkenyl, optionally substituted lower arylalkynyl,        optionally substituted lower heterocyclylalkynyl, optionally        substituted lower alkyl, optionally substituted lower arylalkyl,        optionally substituted aryl, optionally substituted lower        heterocyclylalkyl, and optionally substituted heterocyclyl; or    -   two R¹³'s, when taken together, form 1) a corresponding        spirocyclic ketal from R¹¹, R¹² and the carbon to which they are        attached, when R¹¹ and R¹² are both —OR¹³, or 2) a corresponding        cyclic ketal from R¹⁰ and one of R¹¹ and R¹², and the        corresponding carbons to which they are attached, when R¹⁰ is        —OR¹³, and at least one of R¹¹ and R¹² is also —OR¹³.

Embodiment [0053]

In another example, the compound is according to Embodiment [0052],wherein Y is either —CH₂— or absent.

Embodiment [0054]

In another example, the compound is according to Embodiment [0053],wherein one of R¹¹ and R¹² is —OR¹³, wherein R¹³ is selected from —H,—C(O)R⁴, and optionally substituted lower alkyl; and R¹⁰ and the otherof R¹¹ and R¹² are both —H.

Embodiment [0055]

In another example, the compound is according to Embodiment [0053],wherein one of R¹¹ and R¹² is —F; and R¹⁰ and the other of R¹¹ and R¹²are both —H.

Embodiment [0056]

In another example, the compound is according to Embodiment [0053],wherein R¹³ is an alkyl group containing at least one fluorinesubstitution thereon.

Embodiment [0057]

In another example, the compound is according to Embodiment [0053],wherein q is two or three.

Embodiment [0058]

In another example, the compound is according to Embodiment [0057],wherein each R² is independently selected from —F, —Cl, —Br, —CF₃, —CH₃,and —OR²⁵; wherein R²⁵ is either methyl or aryl, each optionallysubstituted with one to three halogens.

Embodiment [0059]

In another example, the compound is according to Embodiment [0045],wherein said saturated bridged ring system is according to eitherformula V or formula VI;

-   -   wherein R⁸ is selected from —H, optionally substituted lower        alkyl, —CO₂R³, —C(O)N(R³)R⁴, —SO₂R⁴, and —C(O)R³.

Embodiment [0060]

In another example, the compound is according to Embodiment [0059],wherein Y is either —CH₂— or absent.

Embodiment [0061]

In another example, the compound is according to Embodiment [0060],wherein

of I is selected from:

wherein R^(2a)R^(2b), and R^(2c) are each independently selected from F,Cl, and Br.

Embodiment [0062]

In another example, the compound is according to Embodiment [0061],wherein R^(2a) is F, R^(2b) is Cl, and R^(2c) is either Cl or Br.

Embodiment [0063]

In another example, the compound is according to Embodiment [0062],wherein R⁸ is methyl or ethyl.

Embodiment [0064]

In another example, the compound is according to Embodiment [0046],wherein said saturated bridged ring system is according to formula VII:

-   -   wherein A is selected from —O—, —S(O)₀₋₂—, —NR⁸—, —CR⁶R⁷—, and        absent.

Embodiment [0065]

In another example, the compound is according to Embodiment [0064],wherein R³ is selected from —H and optionally substituted alkyl.

Embodiment [0066]

In another example, the compound is according to Embodiment [0065],wherein A is either —C(R⁶)R⁷— or absent.

Embodiment [0067]

In another example, the compound is according to Embodiment [0066],wherein A is either —CH₂— or absent.

Embodiment [0068]

In another example, the compound is according to Embodiment [0067],wherein Y is —CH₂—.

Embodiment [0069]

In another example, the compound is according to Embodiment [0068],wherein q is 3.

Embodiment [0070]

In another example, the compound is according to Embodiment [0069],wherein

of I is selected from:

wherein R^(2a)R^(2b), and R^(2c) are each independently selected from F,Cl, and Br.

Embodiment [0071]

In another example, the compound is according to Embodiment [0070],wherein R^(2a) is F, R^(2b) is Cl, and R^(2c) is either Cl or Br.

Embodiment [0072]

In another example, the compound is according to Embodiment [0043],wherein the saturated bridged ring system has a geometry selected fromthe group consisting of [13.3.1], [13.2.1], and [2.2.1].

Embodiment [0073]

In another example, the compound is according to Embodiment [0072],wherein said saturated bridged ring system contains one or two annularnitrogens, said one or two annular nitrogens are selected from —NR⁸—,when X¹, and a bridgehead nitrogen, when X².

Embodiment [0074]

In another example, the compound is according to Embodiment [0073],wherein said saturated bridged ring system is according to formula VIIIor formula IX;

-   -   wherein R⁸ is selected from —H, optionally substituted lower        alkyl, —CO₂R³, —C(O)N(R³)R⁴, —SO₂R⁴, and —C(O)R³; and R²⁶ is        C₁₋₃ alkyl.

Embodiment [0075]

In another example, the compound is according to Embodiment [0074],wherein Y is —CH₂CH₂—; and E is either absent or —N(R⁹)—.

Embodiment [0076]

In another example, the compound is according to Embodiment [0075],wherein q is 3.

Embodiment [0077]

In another example, the compound is according to Embodiment [0076],wherein

of I is selected from:

wherein R^(2a)R^(2b), and R^(2c) are each independently selected from F,Cl, and Br.

Embodiment [0078]

In another example, the compound is according to Embodiment [0077],wherein R^(2a) is F, R^(2b) is Cl, and R^(2c) is either Cl or Br.

Embodiment [0079]

In another example, the compound is according to Embodiment [0078],wherein R⁸ is methyl or ethyl.

Embodiment [0080]

In another example, the compound is according to Formula I or Ia,selected from Table 1:

TABLE 1 Entry Name Structure 1 N-(3,4-dichloro-2- fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1- methylethyl)octahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine;

N-(3,4-dichloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2-(1-methylethyl)octahydro- cyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

2 N-(4-bromo-3-chloro-2- fluorophenyl)-7- ({[(3aR,5r,6aS)-2-(1-methylethy)octahydro- cyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(4-bromo-3-chloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2-(1-methylethyl)octahydro- cyclopenta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

3 7-({[(3aR,5r,6aS)-2- acetyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-N-(4- bromo-3-chloro-2- fluorophenyl)-6-(methyloxy)quinazolin- 4-amine;

7-({[(3aR,6aS)-2- acetyloctahydrocyclo- penta[c]pyrrol-5-yl]methyl}oxy)-N-(4- bromo-3-chloro-2- fluorophenyl)-6-(methyloxy)quinazolin- 4-amine

4 N-(4-bromo-3-chloro-2- fluorophenyl)-6- (methyloxy)-7- {[(3aR,5r,6aS)-octahydrocyclo- penta[c]pyrrol-5- ylmethyl]oxy}quinazolin- 4-amine;

N-(4-bromo-3-chloro-2- fluorophenyl)-6- (methyloxy)-7-{[(3aR,6aS)-octahydro- cyclopenta[c]pyrrol-5- ylmethyl]oxy}quinazolin-4-amine

5 ethyl (3aR,6aS)-5-({[4- [(4-bromo-3-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)hexahydro- cyclopenta[c]pyrrole-2(1H)-carboxylate

6 N-(4-bromo-3-chloro-2- fluorophenyl)-6- (methyloxy)-7-({[(3aR,5r,6aS)-2- (methylsulfonyl)octahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin- 4-amine;

N-(4-bromo-3-chloro-2- fluorophenyl)-6- (methyloxy)-7- ({[(3aR,6aS)-2-(methylsulfonyl)octahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin- 4-amine

7 N-(3,4-dichloro-2- fluorophenyl)-7- ({[(3aR,5r,6aS)-2-ethyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine;

N-(3,4-dichloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2- ethyloctahydrocyclo-penta[c]pyrrol-5- yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

8 N-(3,4-dichloro-2- fluorophenyl)-6- (methyloxy)-7-({[(3aR,5r,6aS)-2-(2- methylpropyl)octahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin- 4-amine;

N-(3,4-dichloro-2- fluorophenyl)-6- (methyloxy)-7- ({[(3aR,6aS)-2-(2-methylpropyl)octahydro- cyclopenta[c]pyrrol-5- yl]methyl}oxy)quinazolin-4-amine

9 N-(3,4-dichloro-2- fluorophenyl)-7- ({[(3aR,5s,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(3,4-dichloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

10 N-(4-bromo-3-chloro-2- fluorophenyl)-7- ({[(3aR,5s,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(4-bromo-3-chloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

11 N-(3-chloro-2,4- difluorophenyl)-7- ({[(3aR,5s,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(3-chloro-2,4- difluorophenyl)-7- ({[(3aR,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

12 N-(4,5-dichloro-2- fluorophenyl)-7- ({[(3aR,5s,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(4,5-dichloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

13 N-(4-bromo-5-chloro-2- fluorophenyl)-7- ({[(3aR,5s,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(4-bromo-5-chloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

14 N-(4-bromo-2,3- dichlorophenyl)-7- ({[(3aR,5s,6aS)-2-methyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(4-bromo-2,3- dichlorophenyl)-7- ({[(3aR,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5- yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

15 N-(3,4-dichlorophenyl)- 7-({[(3aR,5s,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5- yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine;

N-(3,4-dichlorophenyl)- 7-({[(3aR,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5- yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

16 N-(4-bromo-3-chloro-2- fluorophenyl)-7- ({[(3aR,5r,6aS)-2-ethyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine;

N-(4-bromo-3-chloro-2- fluorophenyl)-7- ({[(3aR,6aS)-2-ethyloctahydrocyclo- penta[c]pyrrol-5- yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

17 N-(4-bromo-3-chloro-2- fluorophenyl)-6- (methyloxy)-7-({[(3aR,5r,6aS)-2-(2- methylpropyl)octahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazol- in-4-amine;

N-(4-bromo-3-chloro-2- fluorophenyl)-6- (methyloxy)-7-({[(3aR,6aS)-2-(2- methylpropyl)octahydro- cyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazol- in-4-amine

18 N-(4-bromo-2,3- dichlorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

19 N-(4,5-dichloro-2- fluorophenyl)-7- {[(3R,9aS)- hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

20 N-(4-bromo-5-chloro-2- fluorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

21 N-(3-chloro-2,4- difluorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

22 N-(3,4-dichloro-2- fluorophenyl)-7- {[(3S,9aS)- hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

23 N-(4-bromo-3-chloro-2- fluorophenyl)-7- {[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

24 N-(3-chloro-2,4- difluorophenyl)-7- {[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

25 N-(3,4-dichlorophenyl)- 7-[(hexahydro-1H- [1,4]oxazino[3,4-c][1,4]oxazin-3- ylmethyl)oxy]-6- (methyloxy)quinazolin- 4-amine

26 N-(4,5-dichloro-2- fluorophenyl)-7- {[(3S,9aS)- hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

27 N-(4-bromo-2,3- dichlorophenyl)-7- {[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

28 N-(4-bromo-5-chloro-2- fluorophenyl)-7- {[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

29 N-(3,4-dichloro-2- fluorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

30 N-(4-bromo-3-chloro-2- fluorophenyl)-7- {[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4- c][1,4]oxazin-3- ylmethyl]oxy}-6-(methyloxy)quinazolin- 4-amine

31 N-(3,4-dichlorophenyl)- 7-{[(3R,8aR)- hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3- ylmethyl]oxy}-6- (methyloxy)quinazolin- 4-amine

32 N-(4-bromo-5-chloro-2- fluorophenyl)-7- {[(3S,8aS)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin- 3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine

33 N-(3,4-dichlorophenyl)- 7-{[(3S,8aR)- hexahydro-1H-pyrrolo[2,1-c][1,4]ox- azin-3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine

34 N-(3,4-dichlorophenyl)- 7-{[(3S,8aS)- hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3- ylmethyl]oxy}-6- (methyloxy)quinazolin- 4-amine

35 N-(3,4-dichlorophenyl)- 7-{[(3R,8aS)- hexahydro-1H- pyrrolo[2,1-c][1,4]oxazin-3- ylmethyl]oxy}-6- (methyloxy)quinazolin- 4-amine

36 N-(3,4-dichloro-2- fluorophenyl)-7- {[(3S,8aS)-hexahydro- 1H-pyrrolo[2,1-c][1,4]oxazin- 3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine

37 N-(4-bromo-3-chloro-2- fluorophenyl)-7- {[(3S,8aS)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin-3- ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine

38 N-(3-chloro-2,4- difluorophenyl)-7- {[(3S,8aS)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin-3- ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine

39 N-(4-bromo-2,3- dichlorophenyl)-7- {[(3S,8aS)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin- 3-ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine

40 N-(4,5-dichloro-2- fluorophenyl)-7- {[(3S,8aS)-hexahydro-1H-pyrrolo[2,1- c][1,4]oxazin-3- ylmethyl]oxy}-6- (methyloxy)quinazolin-4-amine

41 1,4:3,6-dianhydro-5- ({[4-[(4-bromo-5- chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D- xylo-hexitol

42 1,4:3,6-dianhydro-5- deoxy-5-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-2-O- methyl-D-glucitol

43 1,4:3,6-dianhydro-5- deoxy-5-({[4-[(3,4- dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]oxy}methyl)-2-O-methyl-D-xylo-hexitol

44 1,4:3,6-dianhydro-5-({[4- [(4-bromo-3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7- yl]oxy}methyl)-5-deoxy-2-O-methyl-D-xylo- hexitol

45 1,4:3,6-dianhydro-5-({[4- [(3-chloro-2,4- difluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-5-deoxy- 2-O-methyl-D-xylo-hexitol

46 1,4:3,6-dianhydro-5-({[4- [(4-bromo-2,3- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-5- deoxy-2-O-methyl-D- glucitol

47 1,4:3,6-dianhydro-2- deoxy-2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-5-O- methyl-D-threo-hexitol

48 1,4:3,6-dianhydro-5- deoxy-5-({[4-[(4,5- dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]oxy}methyl)-2-O-methyl-D-glucitol

49 (3S,9aS)-3-({[4-[(3,4- dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)hexa- hydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one

50 (3S,9aR)-3-({[4-[(3,4- dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)hexa- hydro-2H-pyrido[1,2-a]pyrazin- 1(6H)-one

51 (3S,8aS)-3-({[4-[(3,4- dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)hexa- hydropyrrolo[1,2-a]pyrazin-1(2H)-one

52 (3S,8aR)-3-({[4-[(3,4- dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)hexa- hydropyrrolo[1,2-a]pyrazin-1(2H)-one

53 (3S,8aS)-3-({[4-[(4- bromo-3-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)hexa- hydropyrrolo[1,2-a]pyrazin-1(2H)-one

54 (3S, 8aS)-3-({[4-[(3,4- dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-2- methylhexahydro-pyrrolo[1,2-a]pyrazin- 1(2H)-one

55 N-(3,4-dichlorophenyl)- 7-({2-[(8-methyl-8- azabicyclo[3.2.1]oct-3-yl)amino]ethyl}oxy)-6- (methyloxy)quinazolin- 4-amine

56 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- {[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3- c][1,4]oxazin-6- ylmethyl]oxy}quinazolin- 4-amine;

N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- [(tetrahydro-1H-[1,3]thiazolo[4,3- c][1,4]oxazin-3- ylmethyl)oxy]quinazolin- 4-amine

57 N-(3,4-dichlorophenyl)- 7-{[2-(8-methyl-8- azabicyclo[3.2.1]oct-3-yl)ethyl]oxy}-6- (methyloxy)quinazolin- 4-amine

58 N-(3,4-dichlorophenyl)- 7-{[(8-methyl-8- azabicyclo[3.2.1]oct-3-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

59 N-(3,4-dichlorophenyl)- 7-{[(3aR,6aS)-2- methyloctahydrocyclo-penta[c]pyrrol-5-yl]oxy}- 6-(methyloxy)quinazolin- 4-amine

60 N-(3,4-dichlorophenyl)- 7-[(8-methyl-8- azabicyclo[3.2.1]oct-3-yl)oxy]-6- (methyloxy)quinazolin- 4-amine

61 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

62 1,4:3,6-dianhydro-2-O- [4-[(3,4-dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-O-methyl-L-iditol

63 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

64 1,4:3,6-dianhydro-2-O- methyl-5-O-{6- (methyloxy)-4-[(2,3,4-trichlorophenyl)ami- no]quinazolin-7-yl}-L- iditol

65 1,4:3,6-dianhydro-5-O- [4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-O-methyl-D-xylo- hexitol

66 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-2,3- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-L-iditol

67 dianhydro-5-O-[4-[(4- bromo-3- chlorophenyl)amino]-6-(methyloxy)-quinazolin- 7-yl]-L-sorbose ethylene glycol acetal

68 1,4:3,6-dianhydro-2-O- [4-[(3-chloro-2,4- difluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-L-iditol

69 1,4:3,6-dianhydro-2-O- [4-[(4,5-dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-L-iditol

70 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O- (difluoromethyl)-L-iditol

71 1,4:3,6-dianhydro-2-O- [4-[(3-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-L-iditol

72 1,4:3,6-dianhydro-2-O- [4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-O-methyl-L-iditol

73 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-L-iditol

74 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-O-ethyl-L-iditol

75 1,4:3,6-dianhydro-2-O- [4-[(3-bromo-2- methylphenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-L- iditol

76 1,4:3,6-dianhydro-2-O- [4-[(3-chloro-2- methylphenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-O-methyl-L-iditol

77 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-deoxy-D-xylo- hexitol

78 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-D- glucitol

79 methyl 3,6-anhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-O-methyl- alpha-L-idofuranoside

80 3,6-anhydro-5-O-[4-[(4- bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-1,2-O-(1- methylethylidene)-beta-L-xylo-hexofuranose

81 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-deoxy-5- methylidene-D-xylo- hexitol

82 methyl 3,6-anhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-O-methyl-beta- L-idofuranoside

83 N-(3,4-dichloro-2- fluorophenyl)-6- (methyloxy)-7- [(octahydro-2H-quinolizin-3-ylmeth- yl)oxy]quinazolin-4- amine

84 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-{6- (methyloxy)-4-[(2,3,4-trifluorophenyl)ami- no]quinazolin-7-yl}-D- iditol

85 1,4:3,6-dianhydro-5-O- [4-[(2-chloro-4- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

86 1,4:3,6-dianhydro-5-O- [4-[(2-bromo-4- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

87 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(2,6- difluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

88 1,4:3,6-dianhydro-5-O-[4- [(3-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

89 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-[4- {[4-fluoro-3-(trifluoro-methyl)phenyl]amino}-6- (methyloxy)quinazolin-7- yl]-D-iditol

90 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(2,4- difluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-fluoro-D-iditol

91 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(2,5- difluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-fluoro-D-iditol

92 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(2,3- difluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-fluoro-D-iditol

93 1,4:3,6-dianhydro-5-O- [4-[(5-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

94 1,4:3,6-dianhydro- 2-deoxy-5-O-[4-[(3,5- difluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

95 1,4:3,6-dianhydro-5-O- [4-[(3-chloro-4- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

96 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-2- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

97 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(3,4- dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

98 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro-D-iditol

99 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-{6- (methyloxy)-4-[(2,4,5-trifluorophenyl)ami- no]quinazolin-7-yl}-D- iditol

100 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-{6- (methyloxy)-4-[(2,4,6-trifluorophenyl)ami- no]quinazolin-7-yl}-D- iditol

101 1,4:3,6-dianhydro-5-O- [4-({4-[(4- chlorophenyl)oxy]-3,5-difluorophenyl}amino)- 6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro-D-iditol

102 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro)-D- iditol

103 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-2,3- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

104 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3-chloro- 5-fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

105 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(4,5- dichloro-2-fluorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

106 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-{6- (methyloxy)-4-[(2,3,4-trichlorophenyl)ami- no]quinazolin-7-yl}-D- iditol

107 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-{6- (methyloxy)-4-[(3,4,5-trichlorophenyl)ami- no]quinazolin-7-yl}-D- iditol

108 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

109 1,4:3,6-dianhydro-5-O- [4-[(4-chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

110 1,4:3,6-dianhydro-5-O- [4-[(3-chloro-2- methylphenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

111 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(3,4- difluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-fluoro-D-iditol

112 1,4:3,6-dianhydro-5-O-[4- [(2-chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

113 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-[4- [(2-fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-D-iditol

114 1,4:3,6-dianhydro-5-O-[4- [(2-chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

115 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-[4- [(4-fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-D-iditol

116 1,4:3,6-dianhydro-5-O-[4- [(4-chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

117 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(2,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

118 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(2,5- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

119 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

120 1,4:3,6-dianhydro-5-O- [4-[(2-bromo-4,6- difluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-deoxy-2-fluoro- D-iditol

121 1,4:3,6-dianhydro-5-O- [4-{[4-chloro-3-(trifluoro-methyl)phenyl]amino}-6- (methyloxy)quinazolin-7- yl]-2-deoxy-2-fluoro-D-iditol

122 1,4:3,6-dianhydro-5-O- [4-{[2-chloro-5-(trifluoro-methyl)phenyl]amino}-6- (methyloxy)quinazolin-7- yl]-2-deoxy-2-fluoro-D-iditol

123 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-[4- {[2-fluoro-3-(trifluoromethyl)phen- yl]amino}-6- (methyloxy)quinazolin-7-yl]-D-iditol

124 1,4:3,6-dianhydro-5-O-[4- {[2-bromo-5-(trifluoro-methyl)phenyl]amino}-6- (methyloxy)quinazolin-7- yl]-2-deoxy-2-fluoro-D-iditol

125 1,4:3,6-dianhydro-5-O-[4- {[2-bromo-4-(trifluoro-methyl)phenyl]amino}-6- (methyloxy)quinazolin-7- yl]-2-deoxy-2-fluoro-D-iditol

126 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-[4- {[4-fluoro-2-(trifluoro-methyl)phenyl]amino}- 6-(methyloxy)quinazolin- 7-yl]-D-iditol

127 1,4:3,6-dianhydro-5-O- [4-{[3-bromo-5-(trifluoro-methyl)phenyl]amino}-6- (methyloxy)quinazolin-7- yl]-2-deoxy-2-fluoro-D-iditol

128 1,4:3,6-dianhydro-5-O- [4-[(2- bromophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

129 1,4:3,6-dianhydro-5-O- [4-[(3- bromophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

130 1,4:3,6-dianhydro-5-O- [4-[(4- bromophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

131 1,4:3,6-dianhydro-5-O- [4-[(3-bromo-4- methylphenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

132 1,4:3,6-dianhydro-5-O- [4-[(5-chloro-2- methylphenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

133 1,4:3,6-dianhydro-2- deoxy-5-O-[4-[(3,5- dimethylphenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-fluoro-D-iditol

134 1,4:3,6-dianhydro-5-O- [4-{[2,5- bis(methyloxy)phen- yl]amino}-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

135 1,4:3,6-dianhydro-5-O- [4-{[5-chloro-2,4- bis(methyloxy)phen-yl]amino}-6- (methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

136 1,4:3,6-dianhydro-5-O- [4-{[4-chloro-2,5- bis(methyloxy)phen-yl]amino}-6- (methyloxy)quinazolin- 7-yl]-2-deoxy-2-fluoro- D-iditol

137 1,4:3,6-dianhydro-5-O- [4-[(3-chloro-2,4- difluorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-deoxy-2-fluoro- D-iditol

138 N-(3,4-dichlorophenyl)- 7-[({5- [{dimethylamino)meth-yl]-1,2,4-oxadiazol-3- yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

139 N-(3,4-dichlorophenyl)- 7-[({3- [(dimethylamino)meth-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

140 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({3- [(4-methylpiperazin-1-yl)methyl]-1,2,4- oxadiazol-5-yl}meth- yl)oxy]quinazolin-4- amine

141 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(5- piperidin-4-yl-1,2,4-oxadiazol-3-yl)meth- yl]oxy}quinazolin-4- amine

142 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)- 1,2,4-oxadiazol-3- yl]methyl}oxy)quinazolin-4-amine

143 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[3-(morpholin-4-ylmethyl)- 1,2,4-oxadiazol-5- yl]methyl}oxy)quinazolin-4-amine

144 N-(3,4-dichlorophenyl)-6- (methyloxy)-7- [(morpholin-2-ylmethyl)oxy]quinazolin- 4-amine

145 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(5- piperidin-2-yl-1,2,4-oxadiazol-3- yl)methyl]oxy}quinazolin- 4-amine

146 N-(3,4-dichlorophenyl)-7- [({2- [(dimethylamino)methyl]-1,3-thiazol-4- yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

147 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4- (phenylmethyl)morph-olin-2-yl]meth- yl}oxy)quinazolin- 4-amine

148 1,1-dimethylethyl 2-({[4- [(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morph- oline-4-carboxylate

149 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[2-(morpholin-4-ylmethyl)- 1,3-thiazol-4-yl]meth- yl}oxy)quinazolin-4-amine

150 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({2- [(4-methylpiperazin-1-yl)methyl]-1,3-thiazol- 4-yl}meth- yl)oxy]quinazolin-4- amine

151 N-(3,4-dichlorophenyl)- 7-{[(4- methylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin- 4-amine

152 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[(1,4- oxazepan-2-ylmeth-yl)oxy]quinazolin-4- amine

153 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(5- piperidin-3-yl-1,2,4-oxadiazol-3-yl)meth- yl]oxy}quinazolin-4- amine

154 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[5- (1-methylpiperidin-2-yl)-1,2,4-oxadiazol-3- yl]methyl}oxy)quina- zolin-4-amine

155 N-(3,4-dichlorophenyl)- 7-{[(4-methyl-1,4- oxazepan-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

156 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[5- (1-methylpiperidin-3-yl)-1,2,4-oxadiazol-3- yl]methyl}oxy)quina- zolin-4-amine

157 N-(3,4-dichlorophenyl)- 7-({[5-(1,1- dimethylethyl)-1,2,4-oxadiazol-3- yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

158 N-(3,4- dichlorophenyl)-6- (methyloxy)-7-{[(2- phenyl-1,3-thiazol-4-yl)methyl]oxy}quinazolin- 4-amine

159 7-[(2,1,3- benzothiadiazol-4- ylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

160 N-(3,4- dichlorophenyl)-7-{[(5- methylisoxazol-3- yl)methyl]oxy}-6-(methyloxy)quinazolin- 4-amine

161 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(5-methyl-4-phenylisoxazol- 3- yl)methyl]oxy}quinazolin- 4-amine

162 7-[(1,3-benzothiazol-2- ylmethyl)oxy]-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

163 7-[(2,1,3-benzoxadiazol- 5-ylmethyl)oxy]-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin- 4-amine

164 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[2-(2-thienyl)-1,3-thiazol- 4-yl]methyl}oxy)quina- zolin-4-amine

165 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(1- phenyl-1H-pyrazol-4-yl)methyl]oxy}quina- zolin-4-amine

166 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({5-[3-(trifluoromethyl)phenyl]- 1,2,4-oxadiazol-3- yl}methyl)oxy]quinazolin-4-amine

167 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({5-[4-(trifluoromethyl)phenyl]- 1,2,4-oxadiazol-3- yl}methyl)oxy]quinazolin-4-amine

168 7-({[3-(4-chlorophenyl)- 1,2,4-oxadiazol-5- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

169 7-({[6-bromo-2- (methyloxy)naphthalen- 1-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

170 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[(1,3- thiazol-4-ylmethyl)oxy]quinazolin- 4-amine

171 7-{[(6-chloropyridin-3- yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

172 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- [(pyridin-4-ylmethyl)oxy]quinazolin- 4-amine

173 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(2- methyl-1,3-thiazol-4-yl)methyl]oxy}quina- zolin-4-amine

174 7-{[(6-chloro-4H-1,3- benzodioxin-8- yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

175 7-{[(5-chloro-1-methyl- 3-phenyl-1H-pyrazol- 4-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

176 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[1- methyl-3-(trifluoromethyl)-1H- thieno[2,3-c]pyrazol-5- yl]methyl}oxy)quinazolin-4-amine

177 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(3- phenylisoxazol-5-yl)methyl]oxy}quinazolin- 4-amine

178 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(2,4,6-trimethylphenyl)meth- yl]oxy}quinazolin-4- amine

179 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- [(pyridin-3-ylmethyl)oxy]quinazolin- 4-amine

180 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({3-[4-(methyloxy)phenyl]iso- xazol-5-yl}meth- yl)oxy]quinazolin-4- amine

181 N-(3,4-dichlorophenyl)- 7-({[5-[(2,4- dichlorophenyl)oxy]-1-methyl-3- (trifluoromethyl)-1H- pyrazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin- 4-amine

182 7- [(cyclopropylmethyl)oxy]- N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

183 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- [(tetrahydrofuran-2-ylmethyl)oxy]quinazolin- 4-amine

184 7-(cyclopentyloxy)-N- (3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4-amine

185 7-[(2- cyclohexylethyl)oxy]-N- (3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

186 7- [(cyclohexylmethyl)oxy]- N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

187 7- [(cyclobutylmethyl)oxy]- N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

188 N-(3,4-dichlorophenyl)- 7-{[2-(1,3-dioxolan-2- yl)ethyl]oxy}-6-(methyloxy)quinazolin-4- amine

189 N-(3,4-dichlorophenyl)- 7-{[2-(1,3-dioxan-2- yl)ethyl]oxy}-6-(methyloxy)quinazolin-4- amine

190 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[(2- morpholin-4-ylethyl)oxy]quinazolin- 4-amine

191 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[(2- pyrrolidin-1-ylethyl)oxy]quinazolin- 4-amine

192 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[(2- piperidin-1-ylethyl)oxy]quinazolin- 4-amine

193 2-(2-{[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}ethyl)-1H- isoindole-1,3(2H)-dione

194 methyl 6-O-[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-alpha-D- glucopyranoside

195 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-[(2- morpholin-4-yl-2-oxoethyl)oxy]quinazolin- 4-amine

196 1,1-dimethylethyl 2-[3- ({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine- 1-carboxylate

197 1,1-dimethylethyl 4-[3- ({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine- 1-carboxylate

198 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4-(4-pyrrolidin-1-ylphenyl)- 1,3-thiazol-2- yl]methyl}oxy)quinazolin-4-amine

199 N-(3,4-dichlorophenyl)- 7-[({4-[4- (diethylamino)phenyl]-1,3-thiazol-2- yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

200 5-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-1,3- thiazol-4-yl]-2- hydroxybenzamide

201 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4-pyridin-3-yl-1,3-thiazol-2- yl)methyl]oxy}quinazolin- 4-amine

202 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(4-pyridin-2-yl-1,3-thiazol-2- yl)methyl]oxy}quinazolin- 4-amine

203 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(4-pyridin-4-yl-1,3-thiazol-2- yl)methyl]oxy}quinazolin- 4-amine

204 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(2- morpholin-4-yl-1,3-thiazol-4- yl)methyl]oxy}quinazolin- 4-amine

205 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(3- morpholin-4-yl-1,2,4-oxadiazol-5- yl)methyl]oxy}quinazolin- 4-amine

206 N-(3,4-dichlorophenyl)- 7-({[3- (dimethylamino)-1,2,4- oxadiazol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

207 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({4- [(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-2- yl}methyl)oxy]quinazolin- 4-amine

208 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4- c]pyridin-2- ylmethyl)oxy]quinazolin-4-amine

209 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4-(morpholin-4-ylmethyl)- 1,3-thiazol-2- yl]methyl}oxy)quinazolin- 4-amine

210 N-(3,4-dichlorophenyl)-7- [({4-[(4-methyl-1,4-diazepan-1-yl)methyl]- 1,3-thiazol-2- yl}methyl)oxy]-6-(methyloxy)quinazolin-4- amine

211 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(5- {[(phenylmeth-yl)oxy]methyl}-1,2,4- oxadiazol-3- yl)methyl]oxy}quinazolin- 4-amine

212 N-(3,4-dichlorophenyl)-7- {[(4-ethylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4- amine

213 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(2-piperidin-4-yl-1,3-thiazol- 4- yl)methyl]oxy}quinazolin- 4-amine

214 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[2-(1-methylpiperidin-4-yl)- 1,3-thiazol-4- yl]methyl}oxy)quinazolin-4-amine

215 1,1-dimethylethyl 4-[5- ({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]piperazine- 1-carboxylate

217 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(3- piperazin-1-yl-1,2,4-oxadiazol-5- yl)methyl]oxy}quinazolin- 4-amine

218 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[3-(4-methylpiperazin-1-yl)- 1,2,4-oxadiazol-5- yl]methyl}oxy)quinazolin-4-amine

219 N-(3,4-dichlorophenyl)- 7-({[5-(1-ethylpiperidin-2-yl)-1,2,4-oxadiazol-3- yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

220 N-(3,4-dichlorophenyl)-7- ({[3-(4-ethylpiperazin-1-yl)-1,2,4-oxadiazol-5- yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

221 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({5- [4-(methyloxy)phenyl]-1,2,4-oxadiazol-3- yl}methyl)oxy]quinazolin- 4-amine

222 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-[({2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-4- yl}methyl)oxy]quinazolin-4-amine

223 7-({[2-(4-chlorophenyl)- 1,3-thiazol-4- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

224 N-(3,4-dichlorophenyl)- 7-({[5-(3,5- dimethylisoxazol-4-yl)-1,2,4-oxadiazol-3- yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

225 7-{[(5-chloro-1- benzothien-3- yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

226 N-(3,4-dichlorophenyl)-7- [({3-[4-(1,1- dimethylethyl)phenyl]-1,2,4-oxadiazol-5- yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

227 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-[({5-[2-(methyloxy)phenyl]-1,2,4- oxadiazol-3- yl}methyl)oxy]quinazolin- 4-amine

228 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[5-(4-methylphenyl)-1,3,4- oxadiazol-2- yl]methyl}oxy)quinazolin- 4-amine

229 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[1- (phenylmethyl)-1H-imidazol-2- yl]methyl}oxy)quinazolin- 4-amine

230 N-(3,4-dichlorophenyl)- 7-({[3-(2,6- dichlorophenyl)-5-methylisoxazol-4- yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

231 N-(3,4-dichlorophenyl)-7- {[(6-fluoro-4H-1,3- benzodioxin-8-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

232 7-{[(3,5-dibromo- phenyl)methyl]oxy}- N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

233 N-(3,4-dichlorophenyl)- 7-{[(2,6-difluoro- phenyl)methyl]oxy}-6-(methyloxy)quinazolin- 4-amine

234 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-[({3- [(pyridin-2-ylsulfonyl)methyl-1,2,4- oxadiazol-5- yl}methyl)oxy]quinazolin- 4-amine

235 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(5-phenyl-1,2,4-oxadiazol-3- yl)methyl]oxy}quinazolin- 4-amine

236 7-({[4-chloro-2- (trifluoromethyl)quinolin- 6-yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

237 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[2-(1- methylpyrrolidin-2-yl)ethyl]oxy}quinazolin- 4-amine

238 N-(3,4-dichlorophenyl)- 7-({[5-(1-ethylpiperidin-4-yl)-1,2,4-oxadiazol-3- yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine

239 N-(3,4-dichlorophenyl)- 7-({[5-(1-ethylpiperidin-3-yl)-1,2,4-oxadiazol-3- yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine

240 N-(3,4-dichlorophenyl)- 7-({[2-(dimethylamino)- 1,3-thiazol-4-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

241 N-(3,4-dichlorophenyl)- 7-{[(4-ethyl-1,4- oxazepan-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

242 N-(3,4-dichlorophenyl)- 7-({[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-4- yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

243 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({3-[(2S)-pyrrolidin-2-yl]- 1,2,4-oxadiazol-5- yl}methyl)oxy]quinazolin-4-amine

244 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-[({2-[(2S)-pyrrolidin-2-yl]-1,3- thiazol-4- yl}methyl)oxy]quinazolin- 4-amine

245 [4-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-1,3- thiazol-2-yl]methyl benzoate

246 [4-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-1,3- thiazol-2-yl]methanol

247 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(5- methyl-4,5,6,7-tetra-hydro[1,3]thiazolo[5,4- c]pyridin-2- yl)methyl]oxy}quinazolin- 4-amine

248 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({2-[(4S)-1,3-thiazolidin-4- yl]-1,3-thiazol-4- yl}methyl)oxy]quinazolin-4-amine

249 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(2-piperidin-2-yl-1,3-thiazol- 4- yl)methyl]oxy}quinazolin- 4-amine

250 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[2-(1-methylpiperidin-2-yl)- 1,3-thiazol-4- yl]methyl}oxy)quinazolin-4-amine

251 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(2-piperidin-3-yl-1,3-thiazol- 4- yl)methyl]oxy}quinazolin- 4-amine

252 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[2-(1-methylpiperidin-3-yl)-1,3- thiazol-4- yl]methyl}oxy)quinazolin- 4-amine

253 N-(3,4-dichlorophenyl)-7- ({[2-(1-ethylpiperidin-2-yl)-1,3-thiazol-4- yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

254 N-(3,4-dichlorophenyl)- 7-({[2-(1- ethylpiperidine-3-yl)-1,3-thiazol-4-yl]methyl}oxy)- 6-(methyloxy)quinazolin- 4-amine

255 N-(3,4-dichlorophenyl)- 7-[({3-[(2S)-1- ethylpyrrolidin-2-yl]-1,2,4-oxadiazol-5- yl}methyl)oxy]-6- (methyloxy)quinazolin- 4-amine

256 N-(3,4-dichlorophenyl)- 7-[({2-[(2S)-1- ethylpyrrolidin-2-yl]-1,3-thiazol-4-yl}methyl)oxy]- 6-(methyloxy)quinazolin- 4-amine

257 N-(3,4-dichlorophenyl)-7- {[(5-ethyl-4,5,6,7-tetra-hydro[1,3]thiazolo[5,4- c]pyridin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4- amine

258 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(4- propyl-1,4-oxazepan-2-yl)methyl]oxy}quinazolin- 4-amine

259 7-({[4- (cyclopropylmethyl)-1,4- oxazepan-2- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

260 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({4-[2-(methyloxy)ethyl]-1,4- oxazepan-2- yl}methyl)oxy]quinazolin- 4-amine

261 N-(3,4-dichlorophenyl)- 7-({[4-(1-methylethyl)- 1,4-oxazepan-2-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

262 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(2- piperazin-1-yl-1,3-thiazol-4- yl)methyl]oxy}quinazolin- 4-amine

263 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(5- pyrrolidin-2-yl-1,2,4-oxadiazol-3- yl)methyl]oxy}quinazolin- 4-amine

264 N-(3,4-dichlorophenyl)- 7-({[5-(1-ethylpyrrolidin-2-yl)-1,2,4-oxadiazol-3- yl]methyl}oxy)-6- (methyloxy)quinazolin-4-amine

265 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({3-[(2S)-1-methylpyrrolidin- 2-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin- 4-amine

266 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({2-[{2S)-1-methylpyrrolidin- 2-yl]-1,3-thiazol-4- yl}methyl)oxy]quinazolin-4-amine

267 N-(3,4-dichlorophenyl)- 7-({[2-(4-ethylpiperazin-1-yl)-1,3-thiazol-4- yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

268 N-(3,4-dichlorophenyl)- 7-{[(1,4- dimethylpiperazin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

269 7-{[(4- cyclopentylmorpholin- 2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

270 N-(3,4-dichlorophenyl)- 7-({[4-(1- methylethyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

271 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4-(3-phenylpropyl)morpholin- 2- yl]methyl}oxy)quinazolin- 4-amine

272 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({4-[2-(methyloxy)ethyl]morph- olin-2- yl}methyl)oxy]quinazolin- 4-amine

273 ethyl 2-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin- 4-yl]propanoate

274 N-(3,4-dichlorophenyl)- 7-{[(4-hex-5-en-1- ylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

275 2-({2-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholin- 4-yl]ethyl}oxy)ethanol

276 methyl 3-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7- yl]oxy}methyl)morpholin- 4-yl]propanoate

277 6-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]hexanenitrile

278 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4-(tetrahydro-2H-pyran-2- ylmethyl)morpholin-2- yl]methyl}oxy)quinazolin-4-amine

279 4-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]butanenitrile

280 N-(3,4-dichlorophenyl)- 7-[({4-[(4- fluorophenyl)meth-yl]morpholin-2- yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

281 methyl 5-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7- yl]oxy}methyl)morpholin- 4-yl]pentanoate

282 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(4-oct-7-en-1-ylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

283 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4- propylmorpholin-2-yl)methyl]oxy}quinazolin- 4-amine

284 6-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]hexan-1-ol

285 7-{[(4-acetylmorpholin-2- yl)methyl]oxy}-N- (3,4-dichlorophenyl)-6-(methyloxy)quinazolin- 4-amine

286 7-({[4-(cyclopropyl- methyl)morpholin-2- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

287 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4-prop-2-yn-1-ylmorpholin- 2- yl)methyl]oxy}quinazolin- 4-amine

288 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4-pyridin-4-ylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

289 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4- (pyridin-2-ylmethyl)morpholin-2- yl]methyl}oxy)quinazolin- 4-amine

290 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4-pent-2-yn-1-ylmorpholin- 2- yl)methyl]oxy}quinazolin- 4-amine

291 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[2-(4-methylpiperazin-1-yl)- 1,3-thiazol-4- yl]methyl}oxy)quinazolin-4-amine

292 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[5-(1-methylpyrrolidin-2-yl)- 1,2,4-oxadiazol-3- yl]methyl}oxy)quinazolin-4-amine

293 N-(3-chloro-4- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

294 7-{[(4-butyl-1,4-oxazepan- 2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

295 (3,4-dichlorophenyl)[7- (methyloxy)-6-({[4-(2- methylpropyl)-1,4-oxazepan-2-yl]meth- yl}oxy)quinazolin-4- amine

296 7-{[(4-acetyl-1- ethylpiperazin-2- yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

297 (3,4-dichlorophenyl)(6- (methyloxy)-7-{[(4- pentyl-1,4-oxazepan-2-yl)methyl]oxy} quinazolin-4-amine

298 (3,4-dichlorophenyl)[6- (methyloxy)-7-({[4- (tetrahydro-2H-pyran-2-ylmethyl)-1,4-oxazepan-2- yl]methyl}oxy)quinazolin- 4-amine

299 (3,4-dichlorophenyl)[6- (methyloxy)-7-({[4-(3- thienylmethyl)-1,4-oxazepan-2- yl]methyl}oxy)quinazolin- 4-amine

300 N-[4-chloro-2,5- bis(methyloxy)phenyl]-7- {[(4-methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

301 N-(3-bromo-2- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

302 7-{[(4-methylmorpholin- 2-yl)methyl]oxy}-6- (methyloxy)-N- (3,4,5-trichlorophen- yl)quinazolin-4-amine

303 N-(3-chloro-2- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

304 N-(3,4-dichlorophenyl)- 7-{[(4-ethanimidoyl- 1,4-oxazepan-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

305 N-(4-bromo-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

306 N-(5-chloro-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

307 N-(4-chloro-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

308 N-(2,4-dichlorophenyl)- 7-{[(4-methylmorpholin- 2-yl)methyl]oxy}-6-(methyloxy)quinazolin- 4-amine

309 N-(2,4-dibromophenyl)- 7-{[(4-methylmorpholin- 2-yl)methyl]oxy}-6-(methyloxy)quinazolin- 4-amine

310 7-{[(4-methylmorpholin- 2-yl)methyl]oxy}-6- (methyloxy)-N-(2,3,4-trichlorophenyl)quinazolin- 4-amine

311 N-(3,4-dichlorophenyl)-7- {[(1-ethyl-4- methylpiperazin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

312 N′-cyano-2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morpholine- 4-carboximidamide

313 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[2-(pyrrolidin-1-ylmethyl)- 1,3-thiazol-4- yl]methyl}oxy)quinazolin-4-amine

314 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4-(tetrahydro-2H-pyran-4- yl)morpholin-2- yl]methyl}oxy)quinazolin-4-amine

315 N-(3,4-dichlorophenyl)-7- ({[4-(2- ethylbutyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

316 7-({[4-(cyclohexyl- methyl)morpholin-2- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

317 2-[2-({[4-[(3,4- dichlorophenyl)amino]- 6-(methyloxy)quinazolin- 7-yl]oxy}methyl)morpholin- 4-yl]ethanol

318 7-{[(4-but-2-yn-1- ylmorpholin-2- yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

319 7-{[(4- cyclobutylmorpholin-2- yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

320 N-(3,4-dichlorophenyl)- 7-[({4-[2-(1,3-dioxolan-2-yl)ethyl]morpholin-2- yl}methyl)oxy]-6- (methyloxy)quinazolin- 4-amine

321 7-({[4-(2-cyclohexyl- ethyl)morpholin-2- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

322 N-(3,4-dichlorophenyl)- 7-[({4-[2-(1,3-dioxan-2-yl)ethyl]morpholin-2- yl}methyl)oxy]-6- (methyloxy)quinazolin- 4-amine

323 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(4-pent-4-en-1-ylmorpholin- 2- yl)methyl]oxy}quinazolin- 4-amine

324 N-(3,4-dichlorophenyl)- 7-[({4-[(2R)-2- methylbutyl]morpholin-2-yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

325 N-(3,4-dichlorophenyl)- 7-({[4-(4- fluorobutyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

326 3-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]butan-2-one

327 1-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]butan-2-one

328 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4- pentylmorpholin-2-yl)methyl]oxy}quinazolin- 4-amine

329 N-(3,4-dichlorophenyl)-7- {[(4-hexylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4- amine

330 N-(3,4-dichlorophenyl)-7- {[(4-heptylmorpholin-2- yl)methyl]oxy}-6-(methyloxy)quinazolin-4- amine

331 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4- octylmorpholin-2-yl)methyl]oxy}quinazolin- 4-amine

332 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4-(2-phenylethyl)morpholin-2- yl]methyl}oxy)quinazolin- 4-amine

333 7-{[(4-butylmorpholin-2- yl)methyl]oxy}-N-(3,4- dichlorophenyl)-6-(methyloxy)quinazolin-4- amine

334 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4-prop-2-en-1-ylmorpholin- 2- yl)methyl]oxy}quinazolin- 4-amine

335 2-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]-1-phenylethanone

336 N-(3,4-dichlorophenyl)-7- ({[4-(2- fluoroethyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

337 N-(3,4-dichlorophenyl)-7- ({[4-(3-methylbut-2-en-1- yl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

338 7-[({4-[(2E)-3-bromoprop- 2-en-1-yl]morpholin-2-yl}methyl)oxy]-N-(3,4- dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

339 2-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]acetamide

340 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-[({4-[3-(tetrahydro-2H-pyran-2- yloxy)propyl-1,4- oxazepan-2-yl}methyl)oxy]quinazolin- 4-amine

341 N-(3,4-dichlorophenyl)-7- ({[4-(3-methylbutyl)-1,4- oxazepan-2-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

342 7-({[4-(cyclohexylmethyl)- 1,4-oxazepan-2- yl]methyl}oxy)-4-[(3,4-dichlorophenyl)methyl]-6- (methyloxy)quinazoline

343 7-({[4-(2- cyclohexylethyl)-1,4- oxazepan-2- yl]methyl}oxy)-4-[(3,4-dichlorophenyl)methyl]-6- (methyloxy)quinazoline

345 N-(3,4-dichlorophenyl)-7- ({[4-(2-ethylbutyl)-1,4- oxazepan-2-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

346 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4- (methylsulfonyl)-1,4-oxazepan-2- yl]methyl}oxy)quinazolin- 4-amine

347 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4-(1- methylpiperidin-4-yl)morpholin-2- yl]methyl}oxy)quinazolin- 4-amine

348 N-(3-chloro-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

349 N′-cyano-2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-1,4- oxazepane-4-carboximidamide

350 N-(3-bromo-4- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

351 N-(3,4-dichlorophenyl)- 7- {[(1,4-diethylpiperazin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

352 4-({[4-[(4-bromo-2- fluorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-N′- cyanopiperidine-1- carboximidamide

353 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4- (methylsulfonyl)morph-olin-2-yl]meth- yl}oxy)quinazolin-4- amine

354 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({4- [(phenylmethyl)sulfon-yl]morpholin-2- yl}methyl)oxy]quina- zolin-4-amine

355 N-(3,4-dichlorophenyl)- 7-[({4-[(4- fluorophenyl)sulfon-yl]morpholin-2- yl}methyl)oxy]-6- (methyloxy)quinazolin-4- amine

356 N-(3,4-dichlorophenyl)- 7-({[4- (ethylsulfonyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

357 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4- (phenylsulfonyl)morph-olin-2- yl]methyl}oxy)quinazolin- 4-amine

358 7-[({4-[(3- chloropropyl)sulfon- yl]morpholin-2-yl}methyl)oxy]-N-(3,4- dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

359 7-({[4- (butylsulfonyl)morpholin- 2- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

360 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-[({4-[(4-methylphenyl)sulfon- yl]morpholin-2- yl}methyl)oxy]quinazolin- 4-amine

361 N-(3,4-dichlorophenyl)-7- [({4-[(3,5- dimethylisoxazol-4-yl)carbonyl]morpholin-2- yl}methyl)oxy]-6- (methyloxy)quinazolin-4-amine

362 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4-{[3- (methyloxy)phen-yl]acetyl}morpholin-2- yl)methyl]oxy}quinazolin- 4-amine

363 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4-(2-methylpentanoyl)morph- olin-2- yl]methyl}oxy)quinazolin- 4-amine

364 7-[({4-[(4- butylphenyl)carbon- yl]morpholin-2-yl}methyl)oxy]-N-(3,4- dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

365 7-[({4-[(4-chlorophen- yl)acetyl]morpholin-2- yl}methyl)oxy]-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

366 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4-(2-propylpentanoyl)morph- olin-2- yl]methyl}oxy)quinazolin- 4-amine

367 N-(3,4- dichlorophenyl)-6- (methyloxy)-7-({[4-(4-methylpentanoyl)morph- olin-2- yl]methyl}oxy)quinazolin- 4-amine

368 N-(3,4-dichlorophenyl)- 7-[({4-[(2,5- difluorophenyl)carbon-yl]morpholin-2- yl}methyl)oxy]-6- (methyloxy)quinazolin- 4-amine

369 7-({[4- (cyclopentylcarbon- yl)morpholin-2- yl]methyl}oxy)-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

370 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4-(2-phenylbutanoyl)morph- olin-2- yl]methyl}oxy)quinazolin- 4-amine

371 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-[({4- [(2,3,6-trifluorophen-yl)carbonyl]morpholin-2- yl}methyl)oxy]quina- zolin-4-amine

372 N-(3,4-dichlorophenyl)- 7-({[4-(furan-3- ylcarbonyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

373 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[(4- propanoylmorpholin-2-yl)methyl]oxy}quina- zolin-4-amine

374 N-(3,4-dichlorophenyl)- 7-{[(4- hexanoylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

375 N-(3,4-dichlorophenyl)- 7-({[4-(2- ethylhexanoyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

376 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-({[4-(3-phenylpropanoyl)morph- olin-2- yl]methyl}oxy)quinazolin- 4-amine

377 N-(3,4-dichlorophenyl)-7- ({[4-(2,2-dimethylpro- panoyl)morpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- amine

378 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-({[4- (naphthalen-1-ylcarbonyl)morpholin-2- yl]methyl}oxy)quinazolin- 4-amine

379 7-[({4-[(2-chloropyridin-3- yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4- dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

380 7-[({4-[(6-chloropyridin-3- yl)carbonyl]morpholin-2-yl}methyl)oxy]-N-(3,4- dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

381 7-({[4-(1,3-benzodioxol-5- ylcarbonyl)morpholin-2-yl]methyl}oxy)-N-(3,4- dichlorophenyl)-6- (methyloxy)quinazolin-4- amine

382 N-(3,4-dichlorophenyl)-6- [(1-methylethyl)oxy]-7- [(morpholin-2-ylmethyl)oxy]quinazolin- 4-amine

383 N-(3,4-dichlorophenyl)-6- {[2- (methyloxy)ethyl]oxy}-7-[(morpholin-2- ylmethyl)oxy]quinazolin- 4-amine

384 N-(3,4-dichlorophenyl)-6- (ethyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin- 4-amine

385 N-(3,4-dichlorophenyl)-6- (ethyloxy)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}quinazolin- 4-amine

386 N-(4-bromo-2- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

387 N-(4-chloro-3- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

388 N′-cyano-2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-N- methylmorpholine-4-carboximidamide

389 N-(4-bromo-3- chlorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

390 N-(3,4-dichlorophenyl)-6- [(1-methylethyl)oxy]-7-{[(4-methylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

391 N-(3,4-dichlorophenyl)-7- {[(4-methylmorpholin-2-yl)methyl]oxy}-6-{[2- (methyloxy)eth- yl]oxy}quinazolin-4- amine

392 N-(4-bromo-2- chlorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

393 7-{[(4-acetyl-1,4- oxazepan-2- yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- (methyloxy)quinazolin- 4-amine

394 4-[(3,4- dichlorophenyl)amino]-7- {[(4-methylmorpholin-2-yl)methyl]oxy}quinazolin- 6-ol

395 N-(3-bromo-4- chlorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

396 3-[2-({[4-[(3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin- 4-yl]-3-oxopropanoic acid

397 methyl 4-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7- yl]oxy}methyl)morpholin-4-yl]-4-oxobutanoate

398 N-(3,4-dichlorophenyl)- 7-{[(4-methylmorpholin- 3-yl)methyl]oxy}-6-(methyloxy)quinazolin- 4-amine

399 N-(3-bromo-2- chlorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

400 N′-cyano-2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-N-[2- (methyloxy)ethyl]morph-oline-4-carboximidamide

401 N′-cyano-2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-N- ethylmorpholine-4-carboximidamide

402 [(1E)-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morph- olin-4-yl](piperidin-1-yl)methylidene]cyanamide

403 [(1E)-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morph- olin-4-yl](pyrrolidin-1-yl)methylidene]cyanamide

404 [(1E)-[2-({[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}methyl)morph- olin-4-yl](4-methylpiperazin-1- yl)methylidene]cyanamide

405 N-(3,4-dichlorophenyl)- 7-{[(6-ethyl-4,6- dimethylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

406 N-(4-bromo-3- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

407 N-(3,4-dichlorophenyl)- 7-{[(6,6- dimethylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

408 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- {[(4,6,6-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

409 N-(3,4-dichlorophenyl)- 7-{[2-(5,5- dimethylmorpholin-2-yl)ethyl]oxy}-6- (methyloxy)quinazolin- 4-amine

410 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[2-(4,5,5-trimethylmorpholin- 2-yl)ethyl]oxy}quinazolin- 4-amine

411 1,1-dimethylethyl 2-(2- {[4-[(3,4- dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]oxy}ethyl)-5,5- dimethylmorpholine-4-carboxylate

412 N-(3,4-dichlorophenyl)-6- (methyloxy)-7-{[(4,5,5-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

413 N-(4-bromo-2,3- dichlorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

414 N-(4,5-dichloro-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

415 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7-{[2-(4,6,6-trimethylmorpholin- 2-yl)ethyl]oxy}quinazolin- 4-amine

416 N-(4-bromo-2,3- difluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

417 N-(4-bromo-2,5- difluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

418 N-(4-bromo-3,5- difluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

419 N-(3,4-dichloro-2- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin- 4-amine

420 N-(3,4-dichlorophenyl)- 7-({[(2R,5S,6S)-5,6- dimethylmorpholin-2-yl]methyl}oxy)-6- (methyloxy)quinazolin- 4-amine

421 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- ({[(2R,5S,6S)-4,5,6-trimethylmorpholin-2- yl]methyl}oxy)quinazolin- 4-amine

422 N-(3,4-dichlorophenyl)- 6-(methyloxy)-7- ({[(2S,5S,6S)-4,5,6-trimethylmorpholin-2- yl]methyl}oxy)quinazolin- 4-amine

423 N-(4-bromo-3-chloro-2- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

424 N-(4-bromo-5-chloro-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

425 N-(4-bromo-3-chloro-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

426 N-(3,4-dichloro-2- fluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

427 N-(3-chloro-2,4- difluorophenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

428 N-(2,3-dichloro-4- methylphenyl)-7-{[(4- methylmorpholin-2-yl)methyl]oxy}-6- (methyloxy)quinazolin-4- amine

429 6-({[4-[3,4- dichlorophenyl)amino]-6- (methyloxy)quinazolin-7-yl]oxy}methyl)-3,3,4- trimethylmorpholin-2-one

430 N-(4-bromo-2,3- dichlorophenyl)-6- (methyloxy)-7-{[(4,5,5-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

431 N-(4-bromo-5-chloro-2- fluorophenyl)-6- (methyloxy)-7-{[(4,5,5-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

432 N-(4,5-dichloro-2- fluorophenyl)-6- (methyloxy)-7-{[(4,5,5-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

433 N-(3,4-dichloro-2- fluorophenyl)-6- (methyloxy)-7-{[(4,5,5-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

434 N-(4-bromo-3-chloro-2- fluorophenyl)-6- (methyloxy)-7-{[(4,5,5-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

435 N-(3-chloro-2,4- difluorophenyl)-6- (methyloxy)-7-{[(4,5,5-trimethylmorpholin-2- yl)methyl]oxy}quinazolin- 4-amine

436 (6S)-6-({[4-[(4-bromo-3- chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-4- methylpiperazin-2-one

437 (6S)-6-({[4-[(3,4- dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-4- methylpiperazin-2-one

438 (6S)-6-({[4-[(4-bromo-3- chloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-1,4- dimethylpiperazin-2-one

439 (6S)-6-({[4-[(3,4- dichloro-2- fluorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]oxy}methyl)-1,4- dimethylpiperazin-2-one

440 N-(4-bromo-3- chlorophenyl)-7- {[(3a′S,4R,6′S,6a′R)-2,2-dimethyltetrahydro- spiro[1,3-dioxolane-4,3′- furo[3,2-b]furan]-6′-yl]oxy}-6- (methyloxy)quinazolin- 4-amine

441 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-O-methyl-5-C- [(methyloxy)methyl]-L-glucitol

442 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-O-(methylsulfonyl)- L-glucitol

443 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-L-glucitol

444 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-5-S-methyl-5-thio-D- iditol

445 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin-7- yl]-2-deoxy-2- morpholin-4-yl-D-iditol

446 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2-(4- methylpiperazin-1-yl)-D-iditol

447 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2- pyrrolidin-1-yl-D-iditol

448 2-O-acetyl-1,4:3,6- dianhydro-5-O-[4-[(4- bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]-D-iditol

449 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-D-iditol

450 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2- (methylsulfonyl)-D- iditol

451 2-amino-1,4:3,6- dianhydro-5-O-[4-[(4- bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]-2-deoxy-D-iditol

452 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy]quinazolin- 7-yl]-2-deoxy-2- (dimethylamino)-D- iditol

453 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2- (diethylamino)-D-iditol

454 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2- piperidin-1-yl-D-iditol

455 2-(acetylamino)-1,4:3,6- dianhydro-5-O-[4-[(4- bromo-3-chlorophenyl)amino]-6- (methyloxy)quinazolin- 7-yl]-2-deoxy-D-iditol

456 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-O-methyl-5-C- (trifluoromethyl)-L-glucitol

457 1,4:3,6-dianhydro-5-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-2-deoxy-2- [(methylsulfonyl)amino]-D-iditol

458 N-(4-bromo-3- chlorophenyl)-6- (methyloxy)-7-[(1-methylpyrrolidin-3- yl)oxy]quinazolin-4- amine

459 N-(4-bromo-3- chlorophenyl)-6- (methyloxy)-7-[(3R)-tetrahydrofuran-3- yloxy]quinazolin-4- amine

460 N-(4-bromo-3- chlorophenyl)-6- (methyloxy)-7- {[(3S,4R)-4-(methyloxy)tetra- hydrofuran-3- yl]oxy}quinazolin-4- amine

461 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O- (6-(methyloxy)-4-{[4-(4-methylpiperazin-1- yl)phenyl]ami- no}quinazolin-7-yl)- D-iditol

462 1,4:3,6-dianhydro-2- deoxy-2-fluoro-5-O-[4- {[3-fluoro-4-(4-methylpiperazin-1- yl)phenyl]amino}-6- (methyloxy)quinazolin-7-yl]-D-iditol

463 1,4:3,6-dianhydro-2- deoxy-5-O-[4- {[2,3-dichloro-4-(4-methylpiperazin-1- yl)phenyl]amino}-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol

464 1,4:3,6-dianhydro-2- deoxy-5-O-[4-{[3,4- dichloro-2-(4-methylpiperazin-1- yl)phenyl]amino}-6- (methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol

465 1,4:3,6-dianhydro-2-O- [4-[(4-bromo-3- chlorophenyl)amino]-6-(methyloxy)quinazolin- 7-yl]-5-C- (trifluoromethyl)-D- glucitol

466 (3,4-dichlorophenyl)[6- (methyloxy)-7-({[4- (tetrahydrofuran-2-ylmethyl)-1,4-oxazepan-2- yl]methyl}oxy)quinazolin- 4-amine

Embodiment 81

Another aspect of the invention is a pharmaceutical compositioncomprising a compound according to any one of embodiments [0024]-[0080]and a pharmaceutically acceptable carrier.

Embodiment 82

Another aspect of the invention is a metabolite of the compound or thepharmaceutical composition according to any one of embodiments[0024]-[0081].

Embodiment 83

Another aspect of the invention is a method of modulating the in vivoactivity of a kinase, the method comprising administering to a subjectan effective amount of the compound or the pharmaceutical compositionaccording to any of embodiments [0024]-[0081].

Embodiment 84

Another aspect of the invention is a method according to embodiment[0083], wherein the kinase is selected from ephrin and EGFR.

Embodiment 85

Another aspect of the invention is a method of modulating the in vivoactivity of a plurality of kinases, the method comprising administeringto a subject an effective amount of the compound or the pharmaceuticalcomposition according to any of embodiments [0024]-[0081].

Embodiment 86

Another aspect of the invention is a method according to embodiment[0085], wherein the plurality of kinases comprises at least one ofephrin and EGFR.

Embodiment 87

Another aspect of the invention is a method according to embodiment[0084], wherein modulating the in vivo activity of the kinase comprisesinhibition of said kinase.

Embodiment 88

Another aspect of the invention is a method according to embodiment[0086], wherein modulating the in vivo activity of the plurality ofkinases comprises inhibition of at least one of ephrin and EGFR.

Embodiment 89

Another aspect of the invention is a method of treating diseases ordisorders associated with uncontrolled, abnormal, and/or unwantedcellular activities, the method comprising administering, to a mammal inneed thereof, a therapeutically effective amount of the compound or thepharmaceutical composition as described in any one of embodiments[0024]-[0081].

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise or they are expressly defined to mean something different.

The atom numbering convention for the quinazoline structure is asfollows:

The symbol “-” means a single bond, “═” means a double bond, “≡” means atriple bond. The symbol “

” refers to a group on a double-bond as occupying either position on theterminus of a double bond to which the symbol is attached; that is, thegeometry, E- or Z-, of the double bond is ambiguous. When a group isdepicted removed from its parent formula, the “

” symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralformula.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

-   -   then, unless otherwise defined, a substituent “R” may reside on        any atom of the ring system, assuming replacement of a depicted,        implied, or expressly defined hydrogen from one of the ring        atoms, so long as a stable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

-   -   then, unless otherwise defined, a substituent “R” may reside on        any atom of the fused ring system, assuming replacement of a        depicted (for example the —NH— in the formula above), implied        (for example as in the formula above, where the hydrogens are        not shown but understood to be present), or expressly defined        hydrogen (for example where in the formula above, “X” equals        —CH—) from one of the ring atoms, so long as a stable structure        is formed. In the example depicted, the “R” group may reside on        either the 5-membered or the 6-membered ring of the fused ring        system. In the formula depicted above, when y is 2 for example,        then the two “R's” may reside on any two atoms of the ring        system, again assuming each replaces a depicted, implied, or        expressly defined hydrogen on the ring.

When there are more than one such depicted “floating” groups, as forexample in the formulae

-   -   where there are two groups, namely, the “R” and the bond        indicating attachment to a parent structure; then, unless        otherwise defined, the “floating” groups may reside on any atoms        of the ring system, again assuming each replaces a depicted,        implied, or expressly defined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

-   -   where, in this example, “y” can be more than one, assuming each        replaces a currently depicted, implied, or expressly defined        hydrogen on the ring; then, unless otherwise defined, where the        resulting structure is stable, two “R's” may reside on the same        carbon. A simple example is when R is a methyl group; there can        exist a geminal dimethyl on a carbon of the depicted ring (an        “annular” carbon). In another example, two R's on the same        carbon, including that carbon, may form a ring, thus creating a        spirocyclic ring (a “spirocyclyl” group) structure with the        depicted ring as for example in the formula:

“Alkyl” is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof, inclusively. For example, “C₈alkyl” may refer to an n-octyl, iso-octyl, cyclohexylethyl, and thelike. Lower alkyl refers to alkyl groups of from one to six carbonatoms. Examples of lower alkyl groups include methyl, ethyl, propyl,isopropyl, butyl s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.Higher alkyl refers to alkyl groups containing more that eight carbonatoms. Exemplary alkyl groups are those of C₂₀ or below. Cycloalkyl is asubset of alkyl and includes cyclic hydrocarbon groups of from three tothirteen carbon atoms. Examples of cycloalkyl groups include c-propyl,c-butyl, c-pentyl, norbomyl, adamantyl and the like. In thisapplication, alkyl refers to alkanyl, alkenyl, and alkynyl residues (andcombinations thereof); it is intended to include cyclohexyvmethyl,vinyl, allyl, isoprenyl, and the like. Thus when an alkyl residue havinga specific number of carbons is named, all geometric isomers having thatnumber of carbons are intended to be encompassed; thus, for example,either “butyl” or “C₄ alkyl” is meant to include n-butyl, sec-butyl,isobutyl, t-butyl, isobutenyl and but-2-yne radicals; and “propyl” or“C₃ alkyl” each include n-propyl, propenyl, and isopropyl.

“Alkylene” refers to straight or branched chain divalent radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation and having from one to ten carbon atoms, for example,methylene, ethylene, propylene, n-butylene and the like. Alkylene is asubset of alkyl, referring to the same residues as alkyl, but having twopoints of attachment and, specifically, fully saturated. Examples ofalkylene include ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—),dimethylpropylene (—CH₂C(CH₃)₂CH₂—), and cyclohexylpropylene(—CH₂CH₂CH(C₆H₁₃)).

“Alkylidene” refers to a straight or branched chain unsaturated divalentradical consisting solely of carbon and hydrogen atoms, having from twoto ten carbon atoms, for example, ethylidene, propylidene, n-butylidene,and the like. Alkylidene is a subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment and,specifically, double bond unsaturation. The unsaturation presentincludes at least one double bond and a double bond can exist betweenthe first carbon of the chain and a carbon atom of the rest of themolecule to which it is attached.

“Alkylidyne” refers to a straight or branched chain unsaturated divalentradical consisting solely of carbon and hydrogen atoms having from twoto ten carbon atoms, for example, propylid-2-ynyl, n-butylid-1-ynyl, andthe like. Alkylidyne is a subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment and,specifically, triple bond unsaturation. The unsaturation presentincludes at least one triple bond and a triple bond can exist betweenthe first carbon of the chain and a carbon atom of the rest of themolecule to which it is attached.

Any of the above radicals, “alkylene,” “alkylidene” and “alkylidyne”when optionally substituted, may contain alkyl substitution which itselfcontains unsaturation. For example,2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains ann-butylid-3-ynyl radical with a vinyl substituent at the 2-position ofsaid radical.

“Alkoxy” or “alkoxyl” refers to the group —O-alkyl, for exampleincluding from one to eight carbon atoms of a straight, branched, cyclicconfiguration, unsaturated chains, and combinations thereof attached tothe parent structure through an oxygen. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Substituted alkoxy” refers to the group —O-(substituted alkyl), thesubstitution on the alkyl group generally containing more than onlycarbon (as defined by alkoxy). One exemplary substituted alkoxy group is“polyalkoxy” or —O-optionally substituted alkylene-optionallysubstituted alkoxy, and includes groups such as —OCH₂CH₂OCH₃, and glycolethers such as polyethyleneglycol and —O(CH₂CH₂O)_(x)CH₃, where x is aninteger of between about two and about twenty, in another example,between about two and about ten, and in a further example between abouttwo and about five. Another exemplary substituted alkoxy group ishydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is for example an integer ofbetween about one and about ten, in another example y is an integer ofbetween about one and about four.

“Acyl” refers to groups of from one to ten carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to six carbons.

“α-Amino Acids” refer to naturally occurring and commercially availableamino acids and optical isomers thereof. Typical natural andcommercially available α-amino acids are glycine, alanine, scrine,homoserine, threonine, valine, norvaline, leucine, isoleucine,norleucine, aspartic acid, glutamic acid, lysine, omithine, histidine,arginine, cysteine, homocysteine, methionine, phenylalanine,homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine,para-tyrosine, tryptophan, glutamine, asparagine, proline andhydroxyproline. A “side chain of an α-amino acid” refers to the radicalfound on the α-carbon of an α-amino acid as defined above, for example,hydrogen (for glycine), methyl (for alanine), benzyl (forphenylalanine), and the like.

“Amino” refers to the group —NH₂. “Substituted amino,” refers to thegroup —N(H)R or —N(R)R where each R is independently selected from thegroup: optionally substituted alkyl, optionally substituted alkoxy,optionally substituted aryl, optionally substituted heterocyclyl, acyl,carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example,diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.

“Aryl” refers to aromatic six- to fourteen-membered carbocyclic ringsinclude, for example, benzene, naphthalene, indane, tetralin, fluoreneand the like.

“Aryalkyl” refers to a residue in which an aryl moiety is attached to aparent structure via one of an alkylene, alkylidene, or alkylidyneradical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyland the like. The aryl, alkylene, alkylidene, or alkylidyne radicalportion of an arylalkyl group may be optionally substituted. “Lowerarylalkyl” refers to an arylalkyl where the “alkyl” portion of the grouphas one to six carbons.

“Exo-alkenyl” refers to a double bond that emanates from an annularcarbon, and is not within the ring system, for example the double bonddepicted in the formula below.

“Fused-polycyclic” or “fused ring system” refers to a polycyclic ringsystem that contains bridged or fused rings; that is, where two ringshave more than one shared atom in their ring structures. Typically, butnot necessarily, fused-polycyclics share a vicinal set of atoms.Typically, a spiro ring system is not a fused-polycyclic by thisdefinition, but fused polycyclic ring systems of the invention maythemselves have spiro rings attached thereto via a single ring atom ofthe fused-polycyclic.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.Dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with a plurality of halogens, but not necessarily aplurality of the same halogen; thus 4-chloro-3-fluorophenyl is withinthe scope of dihaloaryl.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” refers to a stable three- to fifteen-membered ringradical that consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclyl radical may bea monocyclic, bicyclic or tricyclic ring system, which may include fusedor bridged ring systems, and the nitrogen, phosphorus, carbon or sulfuratoms in the heterocyclyl radical may be optionally oxidized to variousoxidation states. In addition, the nitrogen atom may be optionallyquaternized; and the ring radical may be partially or fully saturated oraromatic. Examples of such heterocyclyl radicals include, but are notlimited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyazolyloxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl,isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl,indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl,quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl,thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl,tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, and oxadiazolyl.

“Heteroalicyclic” refers specifically to a non-aromatic heterocyclylsystem radical.

“Heteroaryl” refers specifically to an aromatic heterocyclyl systemradical.

“Heterocyclylalkyl” refers to a residue in which a heterocyclyl isattached to a parent structure via one of an alkylene, alkylidene, oralkylidyne radical. Examples include (4-methylpiperazin-1-yl) methyl,(morpholin-4-yl) methyl, 2-(oxazolin-2-yl) ethyl,4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. The heterocyclyl,alkylene, alkylidene, or alkylidyne radical portion of an arylalkylgroup may be optionally substituted. “Lower heterocyclyalkyl” refers toan arylalkyl where the “alkyl” portion of the group has one to sixcarbons.

“Hydrocarbyl” refers to a hydrocarbon residue, generally. The term“hydrocarbyl” can be modified to mean more specific structures, forexample “a saturated or mono- or poly-unsaturated C₃-C₁₄ mono- orfused-polycyclic hydrocarbyl optionally containing one, two, or threeannular heteroatoms per ring” means a mono- or polycyclic (for example abridged bicyclic) ring system, having between three and fourteen-ringatoms, that contains only carbon ring atoms, but optionally can containup to three heteroatoms per ring and/or unsaturation.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (for example, substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups) that are sterically impractical and/orsynthetically non-feasible. “Optionally substituted” refers to allsubsequent modifiers in a term, for example in the term “optionallysubstituted arylC₁₋₈ alkyl,” optional substitution may occur on both the“C₁₋₈ alkyl” portion and the “aryl” portion of the molecule; and forexample, optionally substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups. Examples of optional substitution include, butare not limited to alkyl, halogen, alkoxy, hydroxy, oxo, carbamyl,acylamino, sulfonamido, carboxy, alkoxycarbonyl, acyl, alkylthio,alkylsulfonyl, nitro, cyano, amino, alkylamino, cycloalkyl and the like.

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, 2,3,3a,4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo[2.2.2]heptaneand 1,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in theclass “saturated bridged ring system.”

“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from aparticular annular carbon of another ring. For example, a ring atom ofthe aforementioned saturated bridged ring system, but not a bridgeheadatom, can be a shared atom between the saturated bridged ring system(rings B and B′) and a spirocyclyl (ring A) attached thereto, asdepicted below. A spirocyclyl can be either carbocyclic or heterocyclic

“Substituted” alkyl, aryl, and heterocyclyl, refer respectively toalkyl, aryl, and heterocyclyl, wherein one or more (for example up toabout five, in another example, up to about three) hydrogen atoms arereplaced by a substituent independently selected from the group:optionally substituted alkyl (for example, fluoroalkyl), optionallysubstituted alkoxy, alkylenedioxy (for example methylenedioxy),optionally substituted amino (for example, alkylamino and dialkylamino),optionally substituted amidino, optionally substituted aryl (forexample, phenyl), optionally substituted arylalkyl (for example,benzyl), optionally substituted aryloxy (for example, phenoxy),optionally substituted arylalkyloxy (for example, benzyloxy), carboxy(—COOH), carboalkoxy (i.e., acyloxy or —OOCR), carboxyalkyl (i.e.,esters or —COOR), carboxamido, aminocarbonyl, benzyloxycarbonylamino(CBZ-amino), cyano, carbonyl, halogen, hydroxy, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclyl, nitro, sulfanyl,sulfinyl, sulfonyl, and thio.

“Sulfanyl” refers to the groups: —S-(optionally substituted alkyl),—S-(optionally substituted aryl), and —S-(optionally substitutedheterocyclyl).

“Sulfinyl” refers to the groups: —S(O)—H, —S(O)-(optionally substitutedalkyl), —S(O)-optionally substituted aryl), and —S(O)-(optionallysubstituted heterocyclyl).

“Sulfonyl” refers to the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-(optionally substituted heterocyclyl), —S(O₂)-(optionallysubstituted alkoxy), —S(O₂)-optionally substituted aryloxy), and—S(O₂)-(optionally substituted heterocyclyloxy).

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

In some embodiments, as will be appreciated by those skilled in the art,two adjacent groups on an aromatic system may be fused together to forma ring structure. The fused ring structure may contain heteroatoms andmay be optionally substituted with one or more groups. It shouldadditionally be noted that saturated carbons of such fused groups (i.e.saturated ring structures) can contain two substitution groups.

Some of the compounds of the invention may have imino, amino, oxo orhydroxy substituents off aromatic heterocyclyl systems. For purposes ofthis disclosure, it is understood that such imino, amino, oxo or hydroxysubstituents may exist in their corresponding tautomeric form, i.e.,amino, imino, hydroxy or oxo, respectively.

Compounds of the invention are generally named using ACD/Name (availablefrom Advanced Chemistry Development, Inc. of Toronto, Canada). Thissoftware derives names from chemical structures according to systematicapplication of the nomenclature rules agreed upon by the InternationalUnion of Pure and Applied Chemistry (IUPAC), International Union ofBiochemistry and Molecular Biology (IUBMB), and the Chemical AbstractsService (CAS).

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure.

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

It is assumed that when considering generic descriptions of compounds ofthe invention for the purpose of constructing a compound, suchconstruction results in the creation of a stable structure. That is, oneskilled in the art would recognize that there can theoretically be someconstructs which would not normally be considered as stable compounds.Stable constructs for the saturated bridged ring system as representedby X¹, X², and optionally X³ of formula II include but are not limitedto motifs such as: 1) where heteroatoms of a ring or bridge thereon arebonded directly to each other, for example a bridge containing asulfonamide, 2) where heteroatoms of a ring or bridge thereon areseparated by only one carbon, for example a urea, carbamate, acetal,aminal, thioacetal, thioaminal, amidine, guanidine, and the like, 3)where heteroatoms of a ring or bridge thereon are separated by two ormore carbons, for example an —NHCH₂CH₂O— bridge, and the like, and 4)where heteroatoms in the bridged ring system are separated by more thantwo carbon atoms, for example wherein the bridged ring system is adecahydro-isoquinoline.

When a particular group with its bonding structure is denoted as beingbonded to two partners, for example a linking group such as —OCH₂—, thenit is understood that either of the two partners may be bound to theparticular group at one end, and the other partner is necessarily boundto the other end of the particular group, unless stated explicitlyotherwise.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. When desired, theR- and S-isomers may be resolved by methods known to those skilled inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. It will be appreciated that where a desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step may be required to liberatethe desired enantiomeric form. Alternatively, specific enantiomer may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting on enantiomer to theother by asymmetric transformation. For a mixture of enantiomers,enriched in a particular enantiomer, the major component enantiomer maybe further enriched (with concomitant loss in yield) byrecrystallization.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a preferred embodiment the patient is a mammal, and ina most preferred embodiment the patient is human.

“Kinase-dependent diseases or conditions” refer to pathologic conditionsthat depend on the activity of one or more protein kinases. Kinaseseither directly or indirectly participate in the signal transductionpathways of a variety of cellular activities including proliferation,adhesion, migration, differentiation and invasion. Diseases associatedwith kinase activities include tumor growth, the pathologicneovascularization that supports solid tumor growth, and associated withother diseases where excessive local vascularization is involved such asocular diseases (diabetic retinopathy, age-related macular degeneration,and the like) and inflammation (psoriasis, rheumatoid arthritis, and thelike).

While not wishing to be bound to theory, phosphatases can also play arole in “kinase-dependent diseases or conditions” as cognates ofkinases; that is, kinases phosphorylate and phosphatasesdephosphorylate, for example protein substrates. Therefore compounds ofthe invention, while modulating kinase activity as described herein, mayalso modulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. In any case, as statedpreviously, the compounds of the invention are useful for treatingdiseases characterized in part by abnormal levels of cell proliferation(i.e. tumor growth), programmed cell death (apoptosis), cell migrationand invasion and angiogenesis associated with tumor growth.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lug: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinorna, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leionmyoma); Genitourinary tract: kidney (adenocarcinoma.Wilm's tumor [neplrroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioina,granuloma, xanthoma, osteitis defomians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomiyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome). Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal lands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

“Pharmaceutically acceptable acid addition salt” refers to those saltsthat retain the biological effectiveness of the free bases and that arenot biologically or otherwise undesirable, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, as well as organic acids such as aceticacid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Exemplary salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplaryorganic bases are isopropylarnine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline, and caffeine. (See, forexample, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977; 66:1-19 which is incorporated herein by reference.)

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)wherein the alkyl group is a straight or branched chain. Acceptableesters also include cycloalkyl esters and arylalkyl esters such as, butnot limited to benzyl. Examples of pharmaceutically acceptable amides ofthe compounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

“Treating” or “treatment” as used herein covers the treatment of adisease-state in a human, which disease-state is characterized byabnormal cellular proliferation, and invasion and includes at least oneof: (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it; (ii) inhibiting the disease-state,i.e., arresting its development; and (iii) relieving the disease-state,i.e., causing regression of the disease-state. As is known in the art,adjustments for systemic versus localized delivery, age, body weight,general health, sex, diet, time of administration, drug interaction andthe severity of the condition may be necessary, and will beascertainable with routine experimentation by those skilled in the art.

General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc. Compositions of the invention may be used incombination with anticancer or other agents that are generallyadministered to a patient being treated for cancer. Adjuvants includepreserving, wetting, suspending, sweetening, flavoring, perfuming,emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecitin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One preferable route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof; and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,diethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 1,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is an example. The specific dosage used,however, can vary. For example, the dosage can depend on a number offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to those skilled in the art.

Utility of Compounds of the Invention as Screening Agents

To employ the compounds of the invention in a method of screening forcandidate agents that bind to, for example ephrin or EGFR receptorkinase, the protein is bound to a support, and a compound of theinvention is added to the assay. Alternatively, the compound of theinvention is bound to the support and the protein is added. Classes ofcandidate agents among which novel binding agents may be sought includespecific antibodies, non-natural binding agents identified in screens ofchemical libraries, peptide analogs, etc. Of particular interest arescreening assays for candidate agents that have a low toxicity for humancells. A wide variety of assays may be used for this purpose, includinglabeled in vitro protein-protein binding assays, electrophoreticmobility shift assays, immunoassays for protein binding, functionalassays (phosphorylation assays, etc.) and the like.

The determination of the binding of the candidate agent to, for exampleephrin or EGFR protein, may be done in a number of ways. In one example,the candidate agent (the compound of the invention) is labeled, forexample, with a fluorescent or radioactive moiety and binding determineddirectly. For example, thus may be done by attaching all or a portion ofephrin or EGFR protein to a solid support, adding a labeled agent (forexample a compound of the invention in which at least one atom has beenreplaced by a detectable isotope), washing off excess reagent, anddetermining whether the amount of the label is that present on the solidsupport. Various blocking and washing steps may be utilized as is knownin the art.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal, forexample, radioisotope, fluorescent tag, enzyme, antibodies, particlessuch as magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

In some embodiments, only one of the components is labeled. For example,ephrin or EGFR protein may be labeled at tyrosine positions using ¹²⁵I,or with fluorophores. Alternatively, more than one component may belabeled with different labels; using ¹²⁵I for the proteins, for example,and a fluorophor for the candidate agents.

The compounds of the invention may also be used as competitors to screenfor additional drug candidates. “Candidate bioactive agent” or “drugcandidate” or grammatical equivalents as used herein describe anymolecule, for example, protein, oligopeptide, small organic molecule,polysaccharide, polynucleotide, etc., to be tested for bioactivity. Theymay be capable of directly or indirectly altering the cellularproliferation phenotype or the expression of a cellular proliferationsequence, including both nucleic acid sequences and protein sequences.In other cases, alteration of cellular proliferation protein bindingand/or activity is screened. In the case where protein binding oractivity is screened, some embodiments exclude molecules already knownto bind to that particular protein. Exemplary embodiments of assaysdescribed herein include candidate agents, which do not bind the targetprotein in its endogenous native state, termed herein as “exogenous”agents. In one example, exogenous agents further exclude antibodies toephrin or EGFR.

Candidate agents can encompass numerous chemical classes, thoughtypically they are organic molecules having a molecular weight of morethan about 100 and less than about 2,500 daltons. Candidate agentscomprise functional groups necessary for structural interaction withproteins, particularly hydrogen bonding and lipophilic binding, andtypically include at least an amine, carbonyl, hydroxyl, ether, orcarboxyl group, for example at least two of the functional chemicalgroups. The candidate agents often comprise cyclical carbon orheterocyclyl structures and/or aromatic or polyaromatic structuressubstituted with one or more of the above functional groups. Candidateagents are also found among biomolecules including peptides,saccharides, fatty acids, steroids, purines, pyrimidines, derivatives,structural analogs, or combinations thereof.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides. Alternatively, libraries of natural compounds in theform of bacterial, fungal, plant and animal extracts are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification to producestructural analogs.

In one example, the binding of the candidate agent is determined throughthe use of competitive binding assays. In this example, the competitoris a binding moiety known to bind to ephrin or EGFR, such as anantibody, peptide, binding partner, ligand, etc. Under certaincircumstances, there may be competitive binding as between the candidateagent and the binding moiety, with the binding moiety displacing thecandidate agent.

In some embodiments, the candidate agent is labeled. Either thecandidate agent, or the competitor, or both, is added first to ephrin orEGFR for a time sufficient to allow binding, if present. Incubations maybe performed at any temperature that facilitates optimal activity,typically between 4° C. and 40° C.

Incubation periods are selected for optimum activity, but may also beoptimized to facilitate rapid high throughput screening. Typicallybetween 0.1 and 1 hour will be sufficient. Excess reagent is generallyremoved or washed away. The second component is then added, and thepresence or absence of the labeled component is followed, to indicatebinding.

In one example, the competitor is added first, followed by the candidateagent. Displacement of the competitor is an indication the candidateagent is binding to ephrin or EGFR and thus is capable of binding to,and potentially modulating, the activity of ephrin or EGFR. In thisembodiment, either component can be labeled. Thus, for example, if thecompetitor is labeled, the presence of label in the wash solutionindicates displacement by the agent. Alternatively, if the candidateagent is labeled, the presence of the label on the support indicatesdisplacement.

In an alternative embodiment, the candidate agent is added first, withincubation and washing, followed by the competitor. The absence ofbinding by the competitor may indicate the candidate agent is bound toephrin or EGFR with a higher affinity. Thus, if the candidate agent islabeled, the presence of the label on the support, coupled with a lackof competitor binding, may indicate the candidate agent is capable ofbinding to ephrin or EGFR.

It may be of value to identify the binding site of, for example, ephrinor EGFR. This can be done in a variety of ways. In one embodiment, onceephrin or EGFR has been identified as binding to the candidate agent,ephrin or EGFR is fragmented or modified and the assays repeated toidentify the necessary components for binding.

Modulation is tested by screening for candidate agents capable ofmodulating the activity of ephrin or EGFR comprising the steps ofcombining a candidate agent with ephrin or EGFR, as above, anddetermining an alteration in the biological activity of ephrin or EGFR.Thus, in this embodiment, the candidate agent should both bind to(although this may not be necessary), and alter its biological orbiochemical activity as defined herein. The methods include both invitro screening methods and in vivo screening of cells for alterationsin cell viability, morphology, and the like.

Alternatively, differential screening may be used to identify drugcandidates that bind to native ephrin or EGFR, but cannot bind tomodified ephrin or EGFR.

Positive controls and negative controls may be used in the assays. Forexample, all control and test samples are performed in at leasttriplicate to obtain statistically significant results. Incubation ofsamples is for a time sufficient for the binding of the agent to theprotein. Following incubation, samples are washed free ofnon-specifically bound material and the amount of bound, generallylabeled agent determined. For example, where a radiolabel is employed,the samples may be counted in a scintillation counter to determine theamount of bound compound.

A variety of other reagents may be included in the screening assays.These include reagents like salts, neutral proteins, for example,albumin, detergents, etc which may be used to facilitate optimalprotein-protein binding and/or reduce non-specific or backgroundinteractions. Also reagents that otherwise improve the efficiency of theassay, such as protease inhibitors, nuclease inhibitors, anti-microbialagents, etc., may be used. The mixture of components may be added in anyorder that provides for the requisite binding.

Abbreviations and their Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

-   -   Ac==acetyl    -   ATP==adenosine triphosphate    -   BNB=4-bromomethyl-3-nitrobenzoic acid    -   Boc==t-butyloxycarbonyl    -   br=broad    -   Bu=butyl    -   C=degrees Celsius    -   c=cyclo    -   CBZ=carbobenzoxy=benzyloxycarbonyl    -   d=doublet    -   dd=doublet of doublet    -   dt=doublet of triplet    -   DBU=diazabicyclo [5.4.0]undec-7-ere    -   DCM=dichloromethane=methylene chloride=CH₂Cl₂    -   DCE==1,2-dichloroethane    -   DEAD=diethyl azodicarboxylate    -   DIC=diisopropylcarbodiimide    -   DIEA=N,N-diisopropylethylamine    -   DMAP=4-N,N-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   DVB=1,4-divinylbenzene    -   EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline    -   EI==Electron Impact ionization    -   Et=ethyl    -   Fmoc=9-fluorenylmethoxycarbonyl    -   g=gram(s)    -   GC=: gas chromatography    -   h or hr=hour(s)    -   HATU==0-(7-Azabenzoazol-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HMDS=hexamethyldisilazane    -   HOAc=acetic acid    -   HOBt=hydroxybenzotriazole    -   HPLC==high pressure liquid chromatography    -   L=liter(s)    -   M=molar or molarity    -   m=multiplet    -   Me=methyl    -   mesyl=methanesulfonyl    -   mg=milligram(s)    -   MHz=megahertz (frequency)    -   Min=minute(s)    -   mL=milliliter(s)    -   mM=millimolar    -   mmol=millimole(s)    -   mol=mole(s)    -   MS=mass spectral analysis    -   MTBE=methyl t-butyl ether    -   N=normal or normality    -   NBS=N-bromosuccinimide    -   NCS=N-chlorosuccinimide    -   nM=nanomolar    -   NMO=N-methylmorpholine oxide    -   NMR=nuclear magnetic resonance spectroscopy    -   PEG=polyethylene glycol    -   pEY=poly-glutamine, tyrosine    -   Ph=phenyl    -   PhOH=phenol    -   PfP=pentafluorophenol    -   PfPy=pentafluoropyridine    -   PPTS=pyridinium p-toluenesulfonate    -   Py=pyridine    -   PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate    -   q=quartet    -   RT=room temperature    -   Sat'd==saturated    -   s=singlet    -   s=secondary    -   t=tertiary    -   t or tr=: triplet    -   TBDMS=t-butyldimethylsilyl    -   TES=triethylsilane    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TMOF=trimethyl orthoformate    -   TMS=trimethylsilyl    -   tosyl=p-toluenesulfonyl    -   Trt=triphenylmethyl    -   uL==microliter(s)    -   uM=micromole(s) or micromolar

Synthesis of Compounds

Scheme I depicts a general synthetic route for compounds of theinvention and is not intended to be limiting. Specific examples aredescribed subsequently to this general synthetic description. A benzoicester 1, where R is typically but not necessarily a methyl radical and Pis typically but not necessarily an alkyl group, is O-alkylated at theoxygen para to the carboxylate group with an electrophile to afford asubstituted derivative 2. P is typically a lower alkyl group, but can bea protecting group that is removed later in a synthesis. When P is alower alkyl group it can possess functionality initially, or bederivitized to contain such functionality at various stages of thesynthesis. The group, E¹, represents either a protecting group, forexample benzyl, or a group that either has moieties present in compoundsof the invention or possesses functionality that serve as a precursorsto such groups. Aromatic ring nitration and reduction of thecorresponding nitro group are carried out in a regio- and chemoselectivemanner by methods well known in the art to give anthranilate derivative3. Formation of quinazolin-4-one 4 is carried out by methods well knownin the art, for example by heating 3 in formamide solution in thepresence of ammonium formate, or for another example by heating directlywith formamidine hydrochloride. Introduction of 4-position functionalityis carried out by methods known in the art. For example,quinazolin-4-one 4 is converted to an intermediate quinazoline 5, where“L” represents a leaving group, for example chlorine. Quinazoline 5 isthen converted to 6 by reaction with a range of nucleophiles, forexample amines, alcohols, and thiols. After formation of 6, group “Z” iseither left “as is” or converted at some subsequent stage to aderivative thereof. For example when Z is —NH—, then the hydrogen on thenitrogen may optionally be replaced with an alkyl group, or when Z issulfur, then that sulfur atom may be oxidized to, for example, asulfone. Compound 6 may represent a compound of the invention or, forexample when E¹ serves as a protecting group, E¹ may be removed toprovide phenol 7. Introduction of a group E² is carried out by methodswell established in the art, for example alkylation with anappropriately derivatized alkyl halide.

EXAMPLES

The following examples serve to more fully describe the manner of usingthe above-described invention, as well as to set forth the best modescontemplated for carrying out various aspects of the invention. It isunderstood that these examples in no way serve to limit the true scopeof this invention, but rather are presented for illustrative purposes.All references cited herein are incorporated by reference in theirentirety. Generally, each example set out below describes a multi-stepsynthesis as outlined above.

Example 11,4:3,6-Dianhydro-2-O-[4-[(3-chloro-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol1,4:3,6-dianhydro-2-O-methyl-5-O-(methylsulfonyl)-D-glucitol

To a solution of 1,4:3,6-dianhydro-2-O-methyl-D-glucitol (1.19 g, 7.4mmol) in dichloromethane was added pyridine (1 mL, 12.36 mmol) followedby methanesulfonyl chloride (0.69 mL, 8.92 mmol) and the mixture wasallowed to stir at room temperature over 12 hours. The solvent wasremoved and the amorphous residue was partitioned between ethyl acetateand aqueous hydrochloric acid (for example 0.1M HC). The aqueous phasewas extracted once with additional ethyl acetate and the combinedorganic layers were washed with saturated aqueous sodium chloride thendried over anhydrous magnesium sulfate. Filtration and concentrationfollowed by drying in vacuo afforded1,4:3,6-dianhydro-2-O-methyl-5-O-(methylsulfonyl)-D-glucitol (1.67 g,94% yield) as a colorless oil. GCMS calculated for C₈H₁₄SO₆: 238 (M⁺).

4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol

4-Chloro-6-(methyloxy)-7-[(phenylmethyl)oxy]quinazoline hydrochloride(22.91 g, 67.9 mmol) was suspended in isopropanol followed by additionof 3,4-dichloroaniline (13.2 g, 81.5 mmol) and concentrated aqueoushydrochloric acid (1 mL). The mixture was brought to reflux over 12hours and diluted with ethyl ether (150 mL). The solid was collected byfiltration, washed with additional ethyl ether and dried. The materialwas then taken into trifluoroacetic acid (150 mL) and brought to refluxover 1 hour. The solution was cooled to room temperature thenconcentrated in vacuo to give a crystalline residue. The residue wassuspended in acetonitrile (100 mL) followed by addition of ethyl ether(100 mL). The solid was collected by filtration and washed withadditional ethyl ether then dried in vacuo to give4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (21.49 g, 64%yield) as a tan solid. ¹H NMR (400 MHz, d₆-DMSO): 11.09 (br s, 1H), 8.87(s, 1H), 8.07 (d, 1H), 8.00 (s, 1H), 7.23 (s, 1H), 3.98 (s, 3H); MS (EI)for C₁₅H₁₁N₃O_(2C)Cl₂: 337 (MH⁺).

1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol hydrochloride

A suspension of4-1[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (1.70 g,3.78 mmol), 1,4:3,6-dianhydro-2-O-methyl-5-O-(methylsulfonyl)-D-glucitol(1.00 g, 4.20 mmol), and potassium carbonate (2.64 g, 19.10 mmol) in DMF(20 mL) was stirred at 80° C. under nitrogen for 15 h. The reactionmixture was poured into water (100 mL), and extracted with ethyl acetate(3×50 mL). The organic layers were washed with 5% LiCl (2×50 mL), andbrine (50 mL) then dried over anhydrous sodium sulfate. Filtration,concentration and column chromatography on silica (97:3dichloromethane/methanol) gave a solid, which was dissolved in methanol(50 mL), and treated with 4M HCl in 1,4-dioxane (5 mL). The resultingprecipitation was filtered, washed with methanol (2×20 mL), and dried toafford 0.99 g (51%) of1,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-ethylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditolhydrochloride as a yellow solid. ¹H NMR (400 MHz, d₆-DMSO): 11.51 (br s,1H), 8.91 (s, 1H), 8.38 (s, 1H), 8.16 (d, 1H), 7.82 (dd, 1H), 7.76 (d,1H), 7.42 (s, 1H), 5.03 (m, 1H), 4.66 (m, 2H), 4.11 (m, 1H), 4.04 (s,3H), 4.02 (m, 1H), 3.90 (m, 3H), 3.31 (s, 3H); MS (EI) forC₂₂H₂₁N₃O₅Cl₂: 478 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

1H NMR (400 MHz, d₆-DMSO): 8.76 (s, 1H), 8.09 (s, 1H), 7.79 (dd, 1H),7.55 (t, 1H), 7.39 (s, 1H), 5.10-5.06 (m, 1H), 4.65 (s, 2H), 4.11 (dd,1H), 4.04-4.02 (m, 1H), 4.00 (s, 3H), 3.94-3.91 (m, 1H), 3.90-3.87 (m,2H), 3.31 (s, 3H); MS (EI) for C₂₂H₂₀BrClFN₃O₅: 540 (MH⁺).

1,4:3,6-dianhydro-2-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 8.77 (s, 1H), 8.13 (s, 1H), 7.96 (d, 1H),7.56 (d, 1H), 7.42 (s, 1H), 5.10-5.06 (m, 1H), 4.66 (s, 2H), 4.12 (dd,1H), 4.05-4.02 (m, 1H), 4.00 (s, 3H), 3.94-3.91 (m, 1H), 3.9-3.91 (m,1H), 3.90-3.87 (m, 2H), 3.31 (s, 3H); MS (EI) for C₂₂H₂₀BrCl₂N₃O₅: 556(MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(3-chloro-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 9.63 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H),7.41 (m, 1H), 7.30 (m, 2H), 7.26 (s, 1H), 5.05 (br s, 1H), 4.63 (dd,2H), 4.03 (ddd AB, 2H), 3.95 (s, 3H), 3.91 (s, 1H), 3.86 (d, 2H), 3.31(s, 31-1H), 2.19 (s, 3H); MS (EI) for C₂₃H₂₄N₃O₅Cl: 458 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 9.69 (s, 1H), 8.42 (s, 1H), 7.94-7.91 (m,2H), 7.82 (s, 1H), 7.29 (s, 1H), 5.06 (br s, 1H), 4.63 (dd, 2H), 4.03(ddd AB, 2H), 3.95 (s, 3H), 3.91-3.86 (m, 3H), 3.31 (s, 3H); MS (EI) forC₂₂H₂₀N₃O₅BrClF: 542 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 11.20 (br s, 1H), 8.81 (s, 1H), 8.06 (s, 1H),7.68-7.62 (m, 1H), 7.51 (d tr, 1H), 7.43 (s, 1H), 5.09 (br s, 1H), 4.66(s, 2H), 4.07 (ddd AB 2H), 3.94 (s, 3H), 4.00-3.88 (m, 3H) 3.31 (s, 3H);MS (EI) for C₂₂H₂₀N₃O₅ClF₂: 480 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 9.69 (s, 1H), 8.42 (s, 1H), 7.94 (d, 1H),7.84 (d, 1H), 7.82 (s, 1H), 7.29 (s, 1H), 4.63 (m, 2H), 4.03 (ddd AB,2H), 3.95 (s, 3H), 3.91-3.86 (m, 3H), 3.31 (s, 3H); MS (EI) forC₂₂H₂₀N₃₅O₅Cl₂F: 496 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 9.68 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H),7.52-7.45 (m, 2H), 7.27 (d tr, 1H), 5.04 (br s, 1H), 4.63 (dd, 2H), 4.02(ddd AB, 2H), 3.94 (s, 3H), 3.89 (br s, 1H), 3.87 (d 2H), 3.30 (s, 3H);MS (EI) for C₂₂H₂₁N₃O₅ClF: 462 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 9.58 (s, 1H), 8.52 (s, 1H), 8.23 (d, 1H),7.82-7.79 (m, 2H) 7.74 (d, 1H), 7.26 (s, 1H) 5.03 (br s, 1H), 4.62 (ddAB, 2H), 4.02 (ddd AB, 2H), 3.96 (s, 3H), 3.89 (br s, 1H), 3.85 (d, 2H)3.30 (s, 3H); MS (EI) for C₂₂H₂₁N₃O₅BrCl: 524 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(3-bromo-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol

1H NMR (400 MHz, d₆-DMSO): 9.65 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H),7.57 (dd, 1H), 7.33 (d, 1H), 7.26-7.21 (m, 2H), 5.04 (br s, 1H), 4.63(dd AB, 2H), 4.03 (ddd AB, 2H), 3.94 (s, 3H), 3.91 (br s, 1H), 3.87 (d,2H), 3.31 (s, 3H); MS (EI) for C₂₃H₂₄N₃O₅Br: 502 (MH⁺).

1,4:3,6-Dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-D-glucitol

MS (EI) for C₂₂H₂₁N₃O₅Cl₂: 478 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-(difluoromethyl)-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 9.64 (s, 1H), 8.56 (s, 1H), 8.26 (d, 1H),7.86-7.82 (m, 2H), 7.77 (d, 1H), 7.31 (s, 1H), 6.84 (tr, 1H), 5.12 (brs, 1H), 4.74 (m, 2H), 4.06 (ddd AB, 2H), 3.98-3.90 (m, 6H); MS (EI) forC₂₂H₁₉N₃O₅BrClF₂: 558 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-ethyl-L-iditol

¹H NMR (400 MHz, d₆-DMSO): 9.62 (s, 1H), 8.55 (s, 1H), 8.26 (d, 1H),7.85-7.82 (m, 2H), 7.76 (d, 1H), 5.04 (br s, 1H), 4.62 (dd AB, 2H),4.15-4.09 (m, 1H), 4.00-3.95 (m, 5H), 3.95-3.82 (m, 2H), 3.57-3.48 (m,2H), 1.13 (tr, 3H); MS (EI) for C₂₃H₂₃N₃O₅BrCl: 536 (MH⁺).

1,4:3,6-Dianhydro-5-deoxy-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-D-xylo-hexitol

¹H NMR (400 MHz, d₆-DMSO): 9.62 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H),7.85-7.82 (m, 2H), 7.76 (d, 1H), 7.30 (s, 1H), 4.98 (m, 1H), 4.80 (m,1H), 4.51 (m, 1H), 4.18-4.14 (m, 1H), 3.97 (s, 3H), 3.92-3.81 (m, 3H),2.01-1.97 (m, 2H); MS (EI) for C₂₁H₁₉N₃O₄BrCl: 492 (MH⁺).

1,4:3,6-Dianhydro-2-O-methyl-5-O-{6-(methyloxy)-4-[(2,3,4-trichlorophenyl)amino]quinazolin-7-yl}-L-iditol

¹H NMR (400 MHz; DMSO-d₆): 9.82 (br s, 1H), 8.36 (s, 1H), 8.86 (s, 1H),7.75-7.73 (d, 1H), 7.60-7.58 (d, 1H), 7.29 (s, 1H), 5.06 (br s, 1H),5.64-5.62 (m, 2H), 4.10-4.07 (dd, 1H), 4.02-4.01 (d, 1H), 3.97-3.94 (m,1H), 3.95 (s, 3H), 3.93-3.90 (m, 1H), 3.88 (br m, 1H), 3.31 (s, 3H); MS(EI) for C₂₂H₂₀C₁₃N₃O₅: 511.91 (MH⁺).

1,4:3,6-Dianhydro-2-O-[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditolhydrochloride

¹H NMR (400 MHz; DMSO-d₆): 8.75 (s, 1H), 8.03 (s, 1H), 7.70-7.53 (m,2H), 7.38 (s, 1H), 5.09-5.07 (m, 1H), 4.64-4.63 (br, 1H), 4.13-4.10 (dd,1H), 4.02-4.01 (d, 1H), 3.99 (s, 3H), 3.93-3.92 (m, 1H), 3.89-3.88 (m,2H), 3.31 (s, 3H); MS (EI) for C₂₂H₂₀Cl₂FN₃O₅: 495.96 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents,1,4:3,6-Dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-glucitolhydrochloride can be prepared

Example 21,4:3,6-Dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)-quinazolin-7-yl]-L-sorboseethylene glycol acetal 1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructoseethylene glycol acetal

A solution of 1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructose (2.00 g,8.06 mmol), ethylene glycol (5.00 g, 80.6 mmol), and p-toluenesulfonicacid (1.53 g, 8.06 mmol) in benzene (100 mL) was refluxed for 90 minusing a Dean-Stark Trap apparatus. The reaction mixture was diluted withethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate(2×50 mL) then brine (50 mL), and dried over anhydrous sodium sulfate.Filtration, concentration and column chromatography on silica. (1:1hexane/ethyl acetate) provided 1.44 g (61% yield) of1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructose ethylene glycol acetalas a colorless solid. ¹H NMR (400 MHz; CDCl₃): 8.08 (m, 2H), 7.58 (m,1H), 7.54 (m, 2H), 5.38 (dd, 1H), 4.97 (t, 1H), 4.21-4.02 (m, 7H), 3.86(d, 1H), 3.75 (d, 1H).

1,4:3,6-dianhydro-D-fructose ethylene glycol acetal

To a solution of 1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructoseethylene glycol acetal (1.44 g, 4.93 mmol) in methanol (40 mL) was added50% aqueous sodium hydroxide (0.38 g, 4.75 mmol) and the mixture wasstirred at room temperature for 30 minutes. Neutralization with 1M HCl,followed by concentration and column chromatography on silica (1:2hexane/ethyl acetate) provided 0.74 g (80% yield) of1,4:3,6-dianhydro-D-fructose ethylene glycol acetal as a colorlesssolid. ¹H NMR (400 MHz; CDCl₃): 4.60 (t, 1H), 4.32 (m, 1H), 4.14 (d,1H), 4.05-3.98 (m, 5H), 3.82 (s, 2H), 3.62 (dd, 1H), 2.65 (d, 1H).

1,4:3,6-dianhydro-5-O-(methylsulfonyl)-D-fructose ethylene glycol acetal

To a solution of 1,4:3,6-dianhydro-D-fructose ethylene glycol acetal(0.74 g, 3.93 mmol) and triethylamine (1.20 g, 11.86 mmol) indichloromethane (40 mL) was added methanesulfonyl chloride (0.90 g, 7.88mmol) at 0° C. under nitrogen. The solution was warmed to roomtemperature and stirred for 13 h. Dichloromethane (50 mL) was added, andthe organic layer was washed with saturated aqueous sodium bicarbonate(30 mL), water (30 mL), and brine (30 mL) then dried over anhydroussodium sulfate. Filtration and concentration provided 1.02 g (97%) of1,4:3,6-dianhydro-5-O-(methylsulfonyl)-D-fructose ethylene glycol acetalas a yellow oil. ¹H NMR (400 MHz; CDCl₃): 5.08 (m, 1H), 4.82 (t, 1H),4.13 (dd, 1H), 4.04 (m, 4H), 3.93 (dd, 1H), 3.87 (d, 1H), 3.81 (d, 1H),3.13 (s, 3H).

1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)-quinazolin-7-yl]-L-sorboseethylene glycol acetal

A suspension of4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (235 mg,0.48 mmol), 1,4:3,6-dianhydro-5-O-(methylsulfonyl)-D-fructose ethyleneglycol acetal (190 mg, 0.71 mmol), and potassium carbonate (329 mg, 2.38mmol) in DMF (10 mL) was stirred at 130° C. under nitrogen for 14 h. Thereaction mixture was poured into water (50 mL), and extracted with ethylacetate (3×30 mL). The organic layers were washed with 5% LiCl (2×25mL), and brine (25 mL) then dried over anhydrous sodium sulfate andconcentrated. Filtration and column chromatography on silica (9:1dichloromethane/acetone to 7:3 dichloromethane/acetone) gave 77 mg (29%)of1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-L-sorboseethylene glycol acetal as a off-white solid. ¹H NMR (400 MHz, CDCl₃):8.70 (s, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 1H), 7.31 (s, 1H),7.14 (s, 1H), 7.00 (s, 1H), 4.98 (m, 1H), 4.86 (d, 1H), 4.42 (d, 1H),4.32-4.23 (m, 2H), 4.10-4.05 (m, 4H), 4.00 (s, 3H), 3.86 (d, 1H), 3.78(d, 1H); MS (EI) for C₂₃H₂₁N₃O₆BrCl: 550 (MH⁺).

Example 31,4:3,6-Dianhydro-2-O-[4-1[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)-quinazolin-7-yl]-5-deoxy-5-methylidene-D-xylo-hexitol1,4:3,6-dianhydro-2-deoxy-2-methylidene-D-arabino-hexitol

To a solution of1,4:3,6-dianhydro-2-deoxy-2-methylidene-5-O-(phenylcarbonyl)-D-arabino-hexitol(329 mg, 1.34 mmol) in methanol (10 mL) was added 50% aqueous sodiumhydroxide (95 mg, 1.19 mmol) and the mixture was stirred at roomtemperature for 30 minutes. Neutralization with 4M hydrogen chloride in1,4-dioxane, followed by concentration and column chromatography onsilica (1:1 hexane/ethyl acetate) provided 141 mg (74%) of1,4:3,6-dianhydro-2-deoxy-2-methylidene-D-arabino-hexitol as a colorlesssolid. ¹H NMR (400 MHz; CDCl₃): 5.37 (m, 1H), 5.20 (m, 1H), 4.80 (m,1H), 4.54 (m, 2H), 4.43 (m, 1H), 4.26 (m, 1H), 3.95 (dd, 1H), 3.54 (dd,1H), 2.70 (d, 1H).

1,4:3,6-dianhydro-2-deoxy-2-methylidene-5-O-(methylsulfonyl)-D-arabino-hexitol

To a solution of1,4:3,6-dianhydro-2-deoxy-2-methylidene-D-arabino-hexitol (135 mg, 0.95mmol) and triethylamine (288 mg, 2.85 mmol) in dichloromethane (10 mL)was added methanesulfonyl chloride (222 mg, 1.94 mmol) at 0° C. undernitrogen. The solution was warmed to room temperature and stirred for 18h. Dichloromethane (50 mL) was added and the organic layer was washedwith saturated aqueous sodium bicarbonate (2×25 mL), water (25 mL) andbrine (25 mL) then dried over anhydrous sodium sulfate. Filtration andconcentration provided 213 mg (72%) of1,4:3,6-dianhydro-2-deoxy-2-methylidene-5-O-(methylsulfonyl)-D-arabino-hexitolas a yellow oil ¹H NMR (400 MHz; CDCl₃): 5.40 (m, 1H), 5.23 (m, 1H),5.04 (m, 1H), 4.85 (m, 1H), 4.73 (t, 1H), 4.58 (m, 1H), 4.41 (m, 1H),4.08 (dd, 1H), 3.86 (dd, 1H), 3.14 (s, 3H).

1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)-quinazolin-7-yl]-5-deoxy-5-methylidene-D-xylo-hexitol

A suspension of4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (425 mg,0.86 mmol),1,4:3,6-dianhydro-2-deoxy-2-methylidene-5-O-(methylsulfonyl)-D-arabino-hexitol(208 mg, 0.94 mmol), and potassium carbonate (594 mg, 4.30 mmol) in DMF(10 mL) was stirred at 130° C. under nitrogen for 15 h. The reactionmixture was poured into water (50 mL), and extracted with ethyl acetate(3×30 mL). The organic layers were washed with 5% LiCl (2×25 mL), andbrine (25 mL), dried over anhydrous sodium sulfate then filtered andconcentrated. Column chromatography on silica (97:3dichloromethane/methanol) gave 234 mg (54%) of1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-deoxy-5-methylidene-D-xylo-hexitolas a yellow solid. ¹H NMR (400 MHz, CDCl₃): 8.70 (s, 1H), 8.01 (d, 1H),7.61 (d, 1H), 7.51 (dd, 1H), 7.36 (s, 1H), 7.14 (s, 1H), 7.01 (s, 1H),5.42 (m, 1H), 5.23 (m, 1H), 5.04 (d, 1H), 4.97 (t, 1H), 4.74 (d, 1H),4.55 (m, 1H), 4.35 (m, 1H), 4.22 (m, 2H), 4.01 (s, 3H); MS (EI) forC₁₂H₁₉N₃O₄BrCl: 504 (MH⁺).

Example 4 Methyl3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-α-L-idofuranoside

To a mixture of 1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-(D)-glucitol(4.32 g, 17.3 mmol), triethylamine (4.91 mL, 35.3 mmol) and4-dimethylaminopyridine (0.63 g, 5.2 mmol) in dichloromethane (50 mL) at−10° to −15° C. was added trifluoromethanesulfonic anhydride (3.48 mL,20.7 mmol) dropwise over ten minutes and the resulting mixture wasstirred at this temperature for 3 hours. The mixture was poured into 100mL of ice-water and extracted with dichloromethane (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered then concentrated. The crude triflate wassuspended in toluene (50 mL) followed by addition of1,8-diazabicyclo[4,5,0]undec-7-ene (5.25 mL, 34.6 mmol) and the mixturewas stirred at room temperature for 18 hours. The reaction mixture waspoured into ice-water and partitioned then the aqueous portion wasextracted with dichloromethane (3×50 mL). The combined organic portionwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flashed chromatography (silicagel, 5-20% ethyl acetate-hexane) to give1,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-D-ararabino-hex-1-enitol,as a white solid, 3.10 g, 77% yield. 1H NMR (400 MHz; CDCl₃): 8.08-8.06(m, 2H), 7.61-7.57 (m, 1H), 7.56-7.43 (m, 2H), 6.62-6.61 (d, 1H),5.48-5.46 (m, 1H), 5.32-5.26 (m, 1H), 5.13-5.10 (m, 2H), 4.18-4.14 (tr,1H), 3.61-3.56 (tr, 1H).

Methyl 3,6-anhydro-5-O-(phenylcarbonyl)-3-D-glucofuranoside

To a solution of1,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-D-arabino-hex-1-enitol(1.00 g, 4.3 mmol) in methanol (17 mL) at −4° C. was added3-chloroperoxybenzoic acid (85%, 135 g, 8.6 mmol), and the resultingmixture was slowly warmed to room temperature and stirred for 18 hours.The reaction mixture was concentrated, diluted with dichloromethane (50mL), washed with saturated aqueous sodium bicarbonate solution, driedover sodium sulfate, filtered and concentrated. The residue was purifiedby flash chromatography (silica gel, 25-60% ethyl acetate-hexane) togive methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-D-glucofuranoside as awhite solid, 1.03 g, 83% yield. ¹H NMR (400 MHz; CDCl₃): 8.11-8.08 (d,2H), 7.61-7.56 (tr, 1H), 7.48-7.44 (m, 2H), 5.24-5.17 (m, 2H), 4.96 (s,1H), 4.57-4.56 (d, 1H), 4.27 (s, 1H), 4.22-4.18 (dd, 1H), 4.08-4.04 (dd,1H) 3.36 (s, 3H).

Methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside

A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-D-glucofuranoside(103 g, 3.7 mmol), silver (I) oxide (0.85 g, 3.7 mmol) and methyl iodide(0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60° C. (for 1 hour.After cooling to room temperature the reaction mixture was diluted withethyl acetate (50 mL), filtered over celite, adsorbed on silica gel (10g) and purified by flash chromatography (silica gel, 5-30% ethylacetate-hexane) to give methyl3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-3-D-glucofuranoside as acolorless oil, 0.82 g, 76% yield. ¹H NMR (400 MHz; CDCl₃): 8.11-8.09 (d,2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09(tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03(tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).

Methyl 3,6-anhydro-2-O-methyl-3-D-glucofuranoside

A solution of methyl3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-3-D-glucofuranoside (820 mg,3.1 mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (10mL) was stirred at room temperature for 30 minutes. The material wasadsorbed on silica gel (5 g) and passed through a short column (15%ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl3,6-anhydro-2-O-methyl-β-D-glucofuranoside as a colorless oil, 420 mg,85% yield. ¹H NMR (400 MHz; CDCl₃): 5.04 (s, 1H), 5.84-5.81 (tr, 1H),4.44-4.42 (tr, 1H), 4.25-4.19 (m, 1H), 3.85-3.75 (m, 1H), 3.49 (s, 3H),3.43 (s, 3H), 2.75-2.72 (d, 1H).

Methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-L-glucofuranoside

Methyl 3,6-anhydro-2-O-methyl-3-D-glucofuranoside (420 mg, 2.6 mmol) wasdissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at0° C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and theresulting mixture was stirred at 0° C. for 1 hour then at roomtemperature for 2 hours. The reaction mixture was washed with water andsaturated aqueous sodium bicarbonate solution, dried over anhydroussodium sulfate, filtered and concentrated to give methyl3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-3-D-glucofuranoside as acolorless oil, 669 mg, 95% yield, which was used without furtherpurification.

Methyl 3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-α-L-idofuranoside

Methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-D-glucofuranoside(314 mg, 1.1 mmol) was dissolved in DMF (3 mL). To this solution wasadded potassium carbonate (404 ing, 2.9 mmol) and4-[(4-bromo-3-chlorophenyl)amino]-6-methyloxy-7-hydroxyquinazolinetrifluoroacetate (280 mg, 0.59 mmol). The resulting mixture was heatedat 135° C. for 18 h. After cooling to room temperature the reactionmixture was diluted with ethyl acetate (15 mL), washed with water, driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by flash chromatography (silica, gel, 2-7% methanol in 1:1ethyl acetate:hexanes) to give methyl3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-O-methyl-α-L-idofuranosideas a white solid, 181 mg, 28% yield. ¹H NMR (400 MHz; Methanol-d₄): 8.75(s, 1H), 8.04-8.06 (d, 1H), 7.99 (s, 1H), 7.78-7.75 (d, 1H), 7.64-7.61(d, 1H), 7.35 (s, 1H), 5.16-5.14 (d, 1H), 5.02 (s, 1H), 4.89 (br, 1H),4.69-4.68 (d, 1H) 4.46-4.42 (dd, 1H), 4.09 (br, 1H), 4.06 (s, 3H), 3.69(s, 1H), 3.48 (s, 3H), 3.42 (s, 3H); MS (EI) for C₂₃H₂₃BrClN₃O₆: 551.88(MH⁺).

Example 63,6-Anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-1,2-O-(1-methylethylidene)-β-D-idofuranose3,6-Anhydro-1,2-O-(methylethylidene)-5-O-(phenylcarbonyl)-α-L-glucofuranose

A mixture of 3,6-anhydro-5-O-(phenylcarbonyl)-α-L-glucofuranose (100 g),2,2-dimethoxy propane (0.63 mL), p-toluenesulfonic acid (20 mg) andbenzene (10 mL) was heated at reflux for 3 hours. The reaction mixturewas cooled then adsorbed on silica gel (10 g) and purified by flashchromatography (silica gel, 5-35% ethyl acetate in hexanes) to give3,6-anhydro-1,2-O-(1-methylethylidene)-5-O-(phenylcarbonyl)-α-L-glucofuranoseas colorless oil, 0.85 g, 74% yield. ¹H NMR (400 MHz; CDCl₃): 8.08-8.06(d, 2H), 7.59-7.56 (tr, 1H), 7.46-7.42 (in, 2H), 5.99-598 (d, 1H),5.35-5.31 (tr, 1H), 5.10-5.08 (d, 1H), 4.66-4.65 (d, 1H), 4.61-4.60 (d,1H), 4.20-4.16 (dd, 1H), 3.91-3.74 (tr, 1H), 1.50 (s, 3H), 1.34 (s, 3H).

3,6-Anhydro-1,2-O-(1-methylethylidene)-5-O-(methylsulfonyl)-α-L-glucofuranose

A solution of3,6-anhydro-1,2-O-(1-methylethylidene)-5-O-(phenylcarbonyl)-α-L-glucofuranose(850 mg) and 50% sodium hydroxide (111 mg) in methanol (10 mL) wasstirred at room temperature for 30 minutes. The mixture was thenadsorbed on silica gel (5 g) and passed through a short column (15%ethyl acetate in hexanes to 5% methanol in ethyl acetate) and thealcohol intermediate, 390 mg, 70% yield, was used immediately in thenext step. The alcohol was dissolved in dichloromethane (10 mL) andpyridine (0.32 mL) at 0° C. Methanesulfonyl chloride (0.12 mL) was addedand the resulting mixture was stirred at 0° C. for 1 hour then at roomtemperature for 2 hours. The reaction mixture was washed with water andsaturated aqueous sodium bicarbonate solution, dried over anhydroussodium sulfate, filtered and concentrated to give3,6-anhydro-1,2-O-(1-methylethylidene)-5-O-(methylsulfonyl)-α-L-glucofuranoseas a colorless oil, 485 mg, 90% yield, which was immediately employed inthe next step.

3,6-Anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-1,2-O-(1-methylethylidene)-β-D-idofuranose

3,6-Anhydro-1,2-O-(1-methylethylidene)-5-O-(methylsulfonyl)-ox-L-glucofuranose, (85 mg, 0.30 mmol) wasdissolved in DMF (3 mL). To this solution was added potassium carbonate(168 mg, 1.21 mmol) and4-[(4-bromo-3-chlorophenyl)amino]-6-methyloxy-7-hydroxyquinazolinetrifluoroacetate (145 mg, 0.30 mmol). The resulting mixture was heatedat 135° C. for 18 h. After cooling to room temperature, the reactionmixture was diluted with ethyl acetate (15 mL), washed with water, driedover anhydrous sodium sulfate, filtered, concentrated. The residue waspurified by flash chromatography (silica gel, 2-7% Methanol in 1:1 ethylacetate:hexanes) to give3,6-anhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-1,2-O-(1-methylethylidene)-β-D-idofuranose,121 mg, 77% yield, as a white solid. ¹H NMR (400 MHz; Methanol-d₄): 8.48(s, 1H), 8.17-8.16 (d, 1H), 7.76 (s, 1H), 7.70-7.61 (m, 2H), 7.19 (s,1H), 5.95-5.94 (d, 1H), 5.18-5.17 (d, 1H), 4.93-4.91 (m, 1H), 4.70-4.62(m, 2H), 4.28-4.22 (dd, 1H), 4.08-4.06 (d, 1H), 4.03 (s, 3H), 1.44 (s,3H), 1.32 (s, 31); MS (EI) for C₂₄H₂₃BrClN₃O₆: 563.83 (MH+).

Example 7(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine and(3R,8aS)-3-(chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine

(S)-(+)-prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47mL, 600 mmol) at 0° C. The solution was stirred at 40° C. for 0.5 h andthen concentrated in vacuo. The residual oil was cooled in an ice bathand concentrated sulfuric acid (18 mL) was added dropwise with stirring.The mixture was heated at 170-180° C. for 1.5 h, poured into ice (300mL) and then basified with sodium carbonate to p˜8. The mixture waspartitioned with ethyl acetate/hexanes and filtered. The filtrate wasseparated and the aqueous portion was extracted twice with ethylacetate. The combined organic portion was dried over sodium sulfate,filtered and concentrated in vacuo to afford an oil which was purifiedby column chromatography (ethyl acetate for less polar product and then30% methanol in ethyl acetate).(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (lesspolar product) (1.87 g, 10.7 mmol, 18% yield): ¹H NMR (400 MHz, CDCl₃):4.06 (dd, 1H), 3.79-3.71 (m, 1H), 3.60-3.48 (m, 2H), 3.36 (dd, 1H), 3.15(dd, 1H), 3.13-3.06 (m, 1H), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H),1.39-1.24 (m, 1H); MS (EI) for C₈H₁₄NOCl: 176 (MH+).(3R,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (1.54g, 8.77 mmol, 15% yield): ¹H NMR (400 MHz, CDCl₃): 3.94-3.77 (m, 4H),3.55 (dd, 1H), 3.02-2.93 (m, 2H), 2.45 (dd, 1H), 2.29-2.15 (m, 2H),1.88-1.64 (m, 3H), 1.49-1.38 (m, 1H); MS (EI) for C₈H₁₄NOCl: 176 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative starting materials, the following reagents wereprepared:

(3R,8aR)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine

¹H NMR (400 MHz, CDCl₃): 4.05 (dd, 1H), 3.79-3.70 (m, 1H), 3.61-3.48 (m,2H), 3.35 (dd, 1H), 3.15 (dd, 1H), 3.13-3.07 (m, 1H), 2.21-2.01 (m, 3H),1.89-1.67 (m, 3H), 1.39-1.25 (m, 1H); MS (EI) for C₈H₁₄NOCl: 176 (MH⁺).

(3S,8aR)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine

¹H NMR (400 MHz, CDCl₃): 3.93-3.77 (m, 4H), 3.55 (dd, 1H), 3.02-2.93 (m,2H), 2.45 (dd, 1H), 2.30-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.37 (m,11H); MS (EI) for C₈H₁₄NOCl: 176 (MH⁺).

Example 8N-(4-Bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochlorideN-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (115ing, 0.655 mmol) and4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetic acid salt (347 mg, 0.655 mmol) were dissolved indimethylacetamide (0.8 mL) and potassium carbonate (452 mg, 3.28 mmol)was added. The mixture was stirred at 130° C. for 36 h. The mixture wascooled to room temperature and the mixture was partitioned between ethylacetate and water. The aqueous portion was extracted with ethyl acetateand the combined organic portion was washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo to afford a brown oilwhich was purified by column chromatography (ethyl acetate-ethanol 1:1).The purified material was dissolved in ethanol and treated with 4Msolution of HCl in 1,4-dioxane (0.25 mL) and the mixture wasconcentrated in vacuo. The residue was dissolved in water andlyophilized to affordN-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride as a brown solid (131 mg, 0.222 mmol, 34% yield). ¹H NMR(400 MHz, d₆-DMSO): 11.9-11.5 (m, 2H), 8.79 (s, 1H), 8.34 (s, 1H), 7.96(d, 1H), 7.54 (d, 1H), 7.41 (s, 1H), 4.47-4.25 (m, 4H), 4.03 (s, 3H)3.96-3.00 (m, 6H), 2.18-1.88 (m, 3H), 1.73-1.57 (m, 1H); MS (EI) forC₂₃H₂₃N₄O₃Cl₂Br: 553 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(3,4-Dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 11.5-11.2 (m, 2H), 8.86 (s, 1H), 8.32 (s,1H), 8.13 (s, 1H), 7.79 (dd, 1H), 7.73 (d, 1H), 7.37 (s, 1H), 4.45-4.24(m, 4H), 4.03 (s, 3H) 3.93-3.00 (m, 6H), 2.20-1.90 (m, 3H), 1.74-1.56(m, 1H); MS (EI) for C₂₃H₂₄N₄O₃Cl₂: 475 (MH⁺).

N-(3,4-Dichlorophenyl)-7-{[(3R,8aR)-hexahydro-1-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 11.6-11.3 (m, 2H), 8.86 (s, 1H), 8.32 (s,1H), 8.14 (s, 1H), 7.80 (dd, 1H), 7.73 (d, 1H), 7.35 (s, 1H), 4.45-4.25(m, 4H), 4.03 (s, 3H) 3.96-2.98 (m, 6H), 2.19-1.89 (m, 3H), 1.72-1.57(m, 1H); MS (EI) for C₂₃H₂₄N₄O₃Cl₂: 475 (MH⁺).

N-(3,4-Dichlorophenyl)-7-{[(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 11.6-11.4 (m, 2H), 8.89 (s, 1H), 8.42 (s,1H), 8.18 (d, 1H), 7.84 (dd, 1H), 7.75 (d, 1H), 7.40 (s, 1H), 4.32 (d,2H), 4.23-4.15 (m, 1H), 4.09-3.95 (m, 2H), 4.05 (s, 3H), 3.70-3.03 (m,5H), 2.14-2.04 (m, 4H); MS (EI) for C₂₃H₂₄N₄O₃Cl₂: 475 (MH+).

N-(3,4-Dichlorophenyl)-7-{[(3S,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMOS): 11.7-11.5 (m, 2H), 8.90 (s, 1H), 8.49 (s,1H), 8.18 (d, 1H), 7.86 (dd, 1H), 7.75 (d, 1H), 7.42 (s, 1H), 4.31 (d,2H), 4.24-4.16 (m, 1H), 4.09-3.95 (m, 2H), 4.06 (s, 3H), 3.69-3.04 (m,5H), 2.14-2.03 (m, 4H); MS (EI) for C₂₃H₂₂N₄O₃Cl₂: 475 (MH⁺).

Example 9N-(3,4-Dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride (3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethylacetate

(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (2.30g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred indimethylformamide (25 mL) at 140° C. for 20 h. The mixture waspartitioned between ethyl acetate and water. The organic portion waswashed twice with water, then with brine, dried over sodium sulfate,filtered and concentrated in vacuo to afford (3,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate as abrown oil (2.53 g, 12.7 mmol, 97% yield). ¹H NMR (400 MHz, CDCl₃):4.14-4.02 (m, 3H), 3.81-3.72 (m, 1H), 3.37-3.31 (m, 1H) 3.09 (dt, 1H),3.00 (dd, 1H), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H),1.39-1.24 (m, 1H); MS (EI) for C₁₀H₁₇NO₃: 200 (MH⁺).

(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylethanol

(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate (2.36g, 11.9 mmol) was treated with sodium methoxide (25 wt % solution inmethanol: 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and asolution of 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) was added slowly.The mixture was stirred at room temperature for 5 minutes and then wasconcentrated in vacuo to afford a suspension which was diluted withdichloromethane, filtered and the filtrate was concentrated in vacuo toafford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol as abrown oil (1.93 g, >100% yield). ¹H NMR (400 MHz, CDCl₃): 4.05 (dd, 1H),3.73-3.65 (m, 2H), 3.62-3.56 (m, 1H), 3.39-3.34 (m, 1H), 3.10 (dt, 1H),3.00-2.95 (m, 1H), 2.24-1.98 (m, 4H), 1.97-1.70 (m, 3H), 1.44-1.28 (m,1H); MS (EI) for C₈H₁₅NO₂: 158 (MH⁺).

(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethylmethanesulfonate

(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol (1.00 g,6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamine(2.4 mL, 17.3 mmol) was added at 0° C. followed by dropwise addition ofmethanesulfonyl chloride (0.93 mL, 12.0 mmol). The solution was warmedto room temperature and stirred for 1.25 h and then was concentrated invacuo. The residue was partitioned between ethyl acetate and saturatedsodium bicarbonate solution. The organic portion was washed withsaturated sodium bicarbonate solution. The combined aqueous portion wasextracted with ethyl acetate. The combined organic portion was washedwith brine, dried over sodium sulfate, filtered and concentrated invacuo to afford(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethylmethanesulfonate as an orange-brown oil (1.20 g, 5.1 mmol, 80% yield).MS (EI) for C₉H₁₇NO₄S: 236 (MH⁺).

N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyoxy)quinazolin-7-oltrifluoroacetic acid salt (307 mg, 0.655 mmol) was dissolved indimethylformamide (1 mL) and potassium carbonate (452 mg, 3.28 mmol) wasadded followed by(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethylmethanesulfonate (250 mg, 1.06 mmol). The mixture was stirred at 70° C.for 41 h and then was partitioned between ethyl acetate and water. Theaqueous portion was extracted with ethyl acetate. The combined organicportion was dried over sodium sulfate, filtered and concentrated invacuo to afford an orange oil which was purified by columnchromatography (ethyl acetate-ethanol 1:1). The purified material wasdissolved in methanol and treated with 4M solution of HCl in 1,4-dioxane(0.1 mL) and the mixture was concentrated in vacuo to affordN-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride as a pale yellow solid (66 mg, 0.125 mmol, 19% yield). ¹HNMR (400 MHz, d₆-DMSO): 11.9-11.5 (m, 2H), 8.83 (s, 1H), 8.39-8.35 (m,1H), 7.69 (dd, 1H), 7.62 (dd, 1H), 7.43 (s, 1H), 4.48-4.24 (m, 4H), 4.04(s, 3H), 3.97-3.85 (m, 1H), 3.78-2.96 (m, 5H), 2.17-1.90 (m, 3H),1.72-1.58 (m, 1H); MS (EI) for C₂₃H₂₃N₄O₃FCl₂: 493 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(3-Chloro-2,4-difluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 11.9-11.6 (m, 2H), 8.84 (s, 1H), 8.41-8.37(m, 1H), 7.67-7.60 (m, 1H), 7.51 (dt, 1H), 7.41 (s, 1H), 4.48-4.24 (m,4H), 4.04 (s, 3H), 3.97-3.86 (m, 1H), 3.80-2.96 (m, 5H), 2.18-1.90 (m,3H), 1.72-1.59 (m, 1H); MS (EI) for C₂₃H₂₃N₄O₃F₂Cl: 477 (MH⁺).

N-(4-Bromo-3-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine

1H NMR (400 MHz, CDCl₃): 8.70 (s, 1H), 8.49 (dd, 1H), 7.49 (dd, 1H),7.29 (s, 1H), 6.98 (s, 1H), 4.25 (dd, 1H), 4.17 (dd, 1H), 4.13-4.06 (m,2H), 4.03 (s, 3H), 3.46-3.38 (m, 1H), 3.20 (dd, 1H), 3.14 (dt, 1H),2.28-2.17 (m, 2H), 2.17-2.07 (m, 1H), 1.90-1.71 (m, 3H), 1.42-1.30 (m,1H): MS (EI) for C₂₃H₂₃N₄₀O₃FClBr: 537 (MH⁺).

N-(4,5-Dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine

¹H NMR (400 MHz, CDCl₃): 8.91 (d, 1H), 8.71 (s, 1H), 7.29-7.26 (m, 2H),6.94 (s, 1H), 4.24 (dd, 1H), 4.16 (dd, 1H), 4.11-4.04 (m, 2H), 4.02 (s,31H), 3.44-3.38 (m, 1H), 3.19 (dd, 1H), 3.13 (dt, 1H), 2.28-2.17 (m,2H), 2.16-2.07 (m, 1H), 1.91-1.69 (m, 3H), 1.42-1.30 (m, 1H); MS (EI)for C₂₃H₂₃N₄O₃FCl₂: 493 (MH⁺).

N-(4-Bromo-5-chloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine

¹H NMR (400 MHz, CDCl₃): 8.95 (d, 1H), 8.72 (s, 1H), 7.43 (d, 1H), 7.28(s, 1H), 6.93 (s, 1H), 4.24 (dd, 1H), 4.15 (dd, 1H), 4.12-4.04 (m, 2H),4.02 (s, 3H), 3.44-3.37 (m, 1H), 3.19 (dd, 1H), 3.13 (dt, 1H), 2.27-2.16(m, 2H), 2.16-2.06 (m, 1H), 1.90-1.69 (m, 3H), 1.42-1.28 (m, 1H); MS(EI) for C₂₃H₂₃N₄O₃FClBr: 537 (MH⁺).

Example 10N-(3,4-Dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H-quinolizin-3-ylmethyl)oxy]quinazolin-4-amine

Octahydro-2H-quinolizin-3-ylmethanol: Ethyloctahydro-21H-quinolizine-3-carboxylate (2.35 g, 11.1 mmol) was addeddropwise to a stirred suspension of lithium aluminum hydride (1 Msolution in tetrahydrofuran, 33 mL, 33 mmol) in tetrahydrofuran (50 mL)at 0° C. The reaction was stirred at room temperature for 3 h. Themixture was cooled in an ice bath and ethyl acetate (6 mL) was addedslowly, followed by water (1.25 mL), 15% aqueous sodium hydroxidesolution (5 mL) and water (1.25 mL). The mixture was filtered through apad of celite and washed with ether. The filtrate was concentrated invacuo and dried rigorously to affordoctahydro-2H-quinolizin-3-ylmethanol as a yellow oil (1.66 g, 9.82 mmol,88% yield). MS (EI) for C₁₀H₁₉NO: 170 (MH⁺).

Octahydro-2H-quinolizin-3-ylmethyl methanesulfonate:

Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolvedin dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) wasadded at 0° C. followed by dropwise addition of methanesulfonyl chloride(0.56 mL, 7.16 mmol). The solution was warmed to room temperature andstirred for 1.25 h and then was concentrated in vacuo. The residue waspartitioned between ethyl acetate and saturated sodium bicarbonatesolution. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to affordoctahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil(796 mg, 3.22 mmol, 91% yield). MS (EI) for C₁₁H₂₁NO₃S: 248 (MH⁺).

N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H-quinolizin-3-ylmethyl)oxy]quinazolin-4-amine

4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-olhydrochloride (469 mg, 1.20 mmol) was dissolved in dimethylformamide (1mL) and potassium carbonate (828 mg, 6.00 mmol) was added followed byoctahydro-2H-quinolizin-3-ylmethyl methanesulfonate (466 mg, 1.89 mmol)in dimethylformamide (1 ml.). The mixture was stirred at 70° C. for 38 hand then was partitioned between ethyl acetate and water. The aqueousportion was extracted with ethyl acetate. The combined organic portionwas dried over sodium sulfate, filtered and concentrated in vacuo toafford a brown oil which was purified by column chromatography (15-20%methanol in dichloromethane). The purified material was crystallizedfrom methanol to affordN-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-[(octahydro-2H-quinolizin-3-ylmethyl)oxy]quinazolin-4-amineas a cream colored solid (83.4 mg, 0.165 mmol, 14% yield). ¹H NMR (400MHz, CDCl₃): 8.69 (s, 1H), 8.53 (t, 1H), 7.34 (dd, 1H), 7.28-7.22 (m,1H), 7.23 (s, 1H), 6.98 (s, 1H), 4.06-3.95 (m, 2H), 4.02 (s, 3H), 3.09(d, 1H), 2.87 (d, 1H), 2.43-2.27 (m, 1H), 2.10-1.97 (m, 1H), 1.95-1.84(m, 2H), 1.80-1.52 (m, 5H), 1.46-0.95 (m, 5H); MS (EI) forC₂₅H₂₇N₄O₂FCl₂: 505 (MH⁺).

Example 11(3S,8aS)-3-({[4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one(3S,8aS)-3-(Hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one

A solution of methyl1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(3.50 g, 10.4 mmol) in methanol was added to 5% palladium on carbon (50wt. % in water) in methanol and treated with hydrogen at 40 psi for 1 h.The mixture was filtered and the filtrate was brought to reflux brieflyand then cooled and concentrated in vacuo to afford(3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2-H)-one as acolorless solid (1.50 g, 8.83 mmol, 85% yield). ¹H NMR (400 MHz, CDCl₃):7.28-7.22 (m, 1H), 3.83-3.75 (m, 1H), 3.69 (dd, 1H), 3.56 (dd, 1H), 3.31(t, 1H), 3.08 (dd, 1H), 2.92 (dt, 1H), 2.76-2.70 (m, 1H), 2.66 (dd, 1H),2.28-2.16 (m, 1H), 2.02-1.73 (m, 3H); MS (EI) for C₉H₁₄N₂O₂: 171 (MH⁺).

(3S,8aS)-3-({[(1,1-Dimethylmethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-c]pyrazin-1(2H)-one

To a solution of (3S,8a)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (1.49 g, 8.82 mmol) indimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol)and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooledin an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol)was added. The mixture was warmed to room temperature and stirred for 14h. The mixture was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and water. The aqueous portion was extracted twicewith ethyl acetate. The combined organic portion was dried over sodiumsulfate, filtered and concentrated in vacuo to afford a pale brown solidwhich was triturated with ethyl acetate to afford(3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-(2H)-one as an off-white solid (1.74 g,5.84 mmol, 66% yield). ¹H NMR (400 MHz, CDCl₃): 6.09-5.90 (m, 1H),3.86-3.76 (m, 1H), 3.63 (dd, 1H), 3.44 (dd, 1H), 3.25 (t, 1H), 3.10(ddd, 1H), 2.98-2.90 (m, 1H), 2.68-2.60 (m, 1H), 2.52 (dd, 1H),2.28-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.93-1.74 (m, 2H), 0.90 (s, 9H),0.07 (s, 6H); MS (EI) for C₁₄H₂₈N₂O₂Si: 285 (MH⁺).

(3S,8aS-3-({[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one

(3S,8aS)-3-({[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-(2H)-one(1.51 g, 5.32 mmol) in dimethylformamide (8 mL) was added to anice-cooled suspension of sodium hydride (60 wt. % dispersion in oil; 213mg, 5.32 mmol) in dimethylformamide (8 mL). The mixture was stirred at0° C. for 0.25 h and then iodomethane (0.332 mL, 5.32 mmol) was addeddropwise. The mixture was stirred at room temperature for 0.5 h and thenwas stirred at 70° C. for 2 h. The mixture was concentrated in vacuo andthe residue was partitioned between ethyl acetate and water. The aqueousportion was extracted with ethyl acetate. The combined organic portionwas dried over sodium sulfate, filtered and concentrated in vacuo toafford(3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methy)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-oneas a yellow oil (1.552 g, 5.21 mmol) which was dissolved intetrahydrofuran (20 mL) and treated with tetrabutylammonium fluoride(1.0M solution in tetrahydrofuran; 10.4 mL, 10.4 mmol) for 2 h at roomtemperature. The mixture was concentrated in vacuo and purified bycolumn chromatography (10% methanol in dichloromethane) to afford(3S,8aS)-3-(hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-oneas a yellow oil (496 mg, 2.70 mmol, 51% yield from(3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-(2H)-one).¹H NMR (400 MHz, CDCl₃): 3.98-3.93 (m, 1H), 3.86 (dd, 1H), 3.61-3.55 (m,1H), 3.29-3.25 (m, 1H), 3.09-3.03 (m, 1H), 3.03-2.97 (m, 1H), 3.02 (s,3H), 2.93 (dd, 1H), 2.87-2.79 (m, 1H), 2.32-2.21 (m, 1H), 2.00-1.86 (m,2H), 1.83-1.64 (m, 1H); MS (EI) for C₉H₁₆N₂O₂: 185 (MH⁺).

(3S,8aS)-3-({[4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one

(3S,8aS)-3-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(21)-one(505 mg, 2.74 mmol) was dissolved in dichloromethane (10 mL) andtriethylamine (0.8 mL, 5.75 mmol) was added at 0° C. followed bydropwise addition of methanesulfonyl chloride (0.45 mL, 5.81 mmol). Thesolution was warmed to room temperature and stirred for 1.25 h and thenwas concentrated in vacuo. The residue was partitioned between ethylacetate and saturated sodium bicarbonate solution. The aqueous portionwas extracted with ethyl acetate. The combined organic portion waswashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo to afford[(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazin-3-yl]methylmethanesulfonate as an orange oil (538 mg, 2.05 mmol, 75% yield).4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-olhydrochloride (469 mg, 1.20 mmol) was dissolved in dimethylformamide (1mL) and potassium carbonate (828 mg, 6.00 mmol) was added followed by[(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazin-3-yl]methylmethanesulfonate (538 mg, 2.05 mmol) in dimethylformamide (1 mL). Themixture was stirred at 70° C. for 34 h and then was concentrated invacuo. The residue was partitioned between ethyl acetate and water. Theaqueous portion was extracted with ethyl acetate. The combined organicportion was dried over sodium sulfate, filtered and concentrated invacuo to afford a brown oil which was purified by column chromatography(6-8% methanol in dichloromethane) to afford a yellow foam (300 mg,0.577 mmol, 48% yield). The yellow foam (100 mg) was purified further bycolumn chromatography (ethyl acetate-ethanol 1:1) to afford(3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-oneas a yellow solid (60 mg). ¹H NMR (400 MHz, CDCl₃): 8.71 (s, 1H), 8.52(dd, 1H), 7.36-7.32 (m, 2H), 7.01 (s, 1H), 4.49 (dd, 1H), 4.34 (dd, 1H),4.03 (s, 3H), 3.90-3.84 (m, 1H), 3.47 (t, 1H), 3.13 (s, 3H), 3.05 (dd,1H), 295 (dd, 1H), 2.93-2.83 (m, 2H), 2.29-2.19 (m, 1H), 2.03-1.84 (m,2H), 1.83-1.70 (m, 1H); MS (EI) for C₂₄H₄N₅O₃FCl₂: 520 (MH⁺).

Example 12(3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one1,2-Dideoxy-1-[(2S)-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy)carbonyl]amino]-D-glycero-hexitol

To a solution of 2-deoxy-2-{[(phenylethyloxy)carbonyl]amino}-D-glycero-hexopyranose (5.0 g, 0.016 mmol) in methanol(500 mL) was added L-proline methyl ester hydrochloride (2.8 g, 0.022mmol) and sodium cyanoborohydride (3.4 g, 0.054 mmol). The solution washeated to 64° C. for 14 h. After cooling to room temperature, thereaction mixture was concentrated in vacuo to afford1,2-dideoxy-1-[(2S)-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy)carbonyl]amino]-D-glycero-hexitol(6.81 g, 100%) as a clear and colorless oil. MS (EI) for C₂₀H₃₁N₂O₈: 427(MH⁺).

Methyl1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate

1,2-dideoxy-1-[(2)-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy)carbonyl]amino]-D-glycero-hexitol (6.81 g, 0.016 mmol) was taken intowater (100 mL) and the resulting solution was cooled to 0° C. Sodiumperiodate (14.8 g, 0.069 mmol) dissolved in water was added dropwise andthe resulting mixture was stirred at 0° C. for 2 h. The reaction mixturewas partitioned with dichloromethane (3×100 mL), dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue wastaken up in methanol (200 mL) and the resulting solution was cooled to0° C. Sodium borohydride (1.98 g, 0.052 mmol) was added and the reactionmixture was stirred for 1 h at 0° C. The reaction mixture wasconcentrated in vacuo and partitioned with dichloromethane and saturatedaqueous ammonium chloride. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The resultingcrude product was purified by column chromatography (5% methanol indichloromethane) to yield methyl1-[(25)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(4.9 g, 92%) as a white solid. MS (EI) for C₁₇H₂₅N₂O₅: 337 (MH⁺).

Methyl1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate: Methyl1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (200 mg, 0.594 mmol) was dissolved indichloromethane (5 mL) followed by the addition of4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) and triethylamine (0.125mL, 0.891 mmol) and the resulting mixture was cooled to 0° C.Methanesulfonyl chloride (0.060 mL, 0.773 mmol) was added dropwise andthe reaction mixture was stirred for 1 h at 0° C. The mixture waspartitioned between dichloromethane and saturated aqueous sodiumbicarbonate. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to afford methyl1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(246 mg, 100%) as a clear and colorless oil. MS (EI) for C₁₈H₂₇N₂O₇S:415 (MH⁺).

methyl(1R)-2-[(2S)-3-{[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]cyclopentanecarboxylate

4-[(3,4-dichloro-2-fluorophenyl)amino-6-(methyloxy)quinazolin-7-olhydrochloride (400 mg, 1.02 mmol) and methyl1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(603 mg, 1.45 mmol) were suspended in DMF (5 mL) and powdered potassiumcarbonate (705 mg, 5.10 mmol) was added. The mixture was stirred at 70°C. for 12 h. The reaction mixture was filtered and concentrated invacuo. The crude residue was purified by column chromatography (10%methanol in dichloromethane) to yield methyl(1R)-2-[(2S)-3-{[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]cyclopentanecarboxylate(686 mg, 100%) as a yellow oil. MS (EI) for C₃₂H₃₂Cl₂FN₅O₆: 672 (M⁺).

(3S,8a)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one

Methyl(1R)-2-[(2S)-3-{[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]cyclopentanecarboxylate (686 mg, 1.02 mmol)was diluted with glacial acetic acid (3 mL) and 30 wt % hydrogen bromidein acetic acid (2 mL) was added. The resulting mixture was stirred for13 h and then concentrated in vacuo. The crude residue was taken up inmethanol (5 mL) followed the addition of powdered potassium carbonate(700 mg, 5.07 mmol) at room temperature. The resulting mixture wasstirred for 7 h, filtered, and concentrated in vacuo. The crude residuewas purified by column chromatography (10% methanol in dichloromethane)to yield the title compound (181 mg, 35%) as a yellow solid. ¹H NMR (400MHz, d₄-MeOH): 8.34 (s, 1H), 7.75 (s, 1H), 7.76-7.55 (m, 1H), 7.45-7.40(dd, 1H), 7.17 (s, 1H), 4.30-4.25 (m, 1H), 4.20-4.15 (m, 2H), 4.03 (s,3H), 3.78-3.70 (m, 1H), 3.65-3.60 (m, 1H), 3.55-3.50 (m, 1H), 3.32-3.29(m, 2H), 3.00-2.95 (m, 2H), 2.83-278 (m, 2H), 2.25-2.15 (m, 2H); MS (EI)for C₂₃H₂₃Cl₂FN₅O₃: 507 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

(3S,8aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one

C₂₃H₂₃ClFN₅O₃: 507 (MH⁺).

(3S,8aS)-3-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-methyl)hexahydropyrrolo[1,2-a]pyrazin-1-(2H)-one

¹H NMR (400 MHz, d₄-MeOH): 8.36 (s, 1H), 7.71 (s, 1H), 7.60-7.55 (m,2H), 7.18 (s, 1H), 4.29-4.22 (m, 1H), 4.19-4.14 (m, 1H), 4.02 (s, 3H),3.99-3.92 (m, 1H), 3.36-3.30 (m, 1H), 3.32-3.90 (m, 2H), 2.82-2.74 (m,1H), 2.26-2.10 (m, 1H), 2.19-2.18 (m, 3H), 1.30-1.20 (m, 2H), 0.90-0.80(m, 1H); MS (EI) for C₂₃H₂₃BrClN₅O₃: 551 (MH⁺).

(3S, 9aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one

C₂₄H₂₅Cl₂N₅O₃: 521 (MH⁺).

(3S, 9aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-a]pyrazin-1(61-1)-one

C₂₄H₂₅Cl₂FN₅O₃: 521 (MH⁺).

Example 13N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride 1,1-Dimethylethyl(3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Under a nitrogen atmosphere, borane tetrahydrofuran complex (IM in THF,42 mL, 41.9 mmol) was diluted with tetrahydrofuran (42 mL) and cooledwith an ice bath. Neat 2,3-dimethylbut-2-ene (5.0 mL, 41.9 mmol) wasadded in portions over 0.25 h and the solution was stirred at 0° C. for3 h. A solution of 1,1-dimethylethyl(3aR,6aS)-5-methylidenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(1.98 g, 8.88 mmol) in tetrahydrofuran (10 mL) was added slowly, and thesolution was warmed to room temperature and stirred 12 h. After coolingto 0° C., 10% aqueous sodium hydroxide (17 mL, 41.7 mmol) was addedslowly, followed by 30% aqueous hydrogen peroxide (13 mL, 128 mmol) andthe solution was warmed to room temperature. The solvent was removed invacuo and the solution was partitioned between water and diethyl ether.The layers were separated and the aqueous layer was further extracted(3×50 mL diethyl ether). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to provide2.04 (95%) of 1,1-dimethylethyl(3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,which was used without purification. ¹H NMR (400 MHz, CDCl₃): 8.50(broad s, 1H), 3.66-3.46 (m, 3H), 3.20-3.00 (m, 2H), 2.70-2.59 (m, 2H),2.37-2.18 (m, 1H), 2.04 (m, 1H), 1.84 (broad s, 1H), 1.70-1.55 (m, 1H),1.46 (s, 9H), 1.17 (m, 1H), 0.93 (m, 1H).

1,1-Dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocyclo-penta[c]pyrrole-2(1H)-carboxylateMethanesulfonyl chloride (0.2 mL, 2.48 mmol), was added dropwise to asolution of 1,1-dimethylethyl (3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.40 g, 1.65 mmol) andtriethylamine (0.69 mL, 4.95 mmol) in 20 mL dichloromethane at 0° C. andthe reaction mixture was stirred for 1 h at room temperature. Thesolvent was evaporated, the resulting crude mixture was diluted with 100mL ethyl acetate and washed with water (30 mL), IM aqueous sodiumhydroxide, brine, 1M aqueous hydrochloric acid and brine again. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The resulting 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatewas used without further purification. MS (EI) for C₁₄H₂₅NO₅S: 320(MH⁺), 264 (M-tBu).

1,1-Dimiethylethyl(3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxyl-ate

A solution of4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (0.217 g, 0.425 mmol), 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.163 g, 0.510 mmol), potassium carbonate (0.290 g, 2.12 mmol) inN,N-dimethylacetamide (1.6 mL) was heated in a sealed reaction tube at90° C. for 12 h. The crude reaction mixture was diluted with 100 mL of10% methanol in ethyl acetate and washed with water (5×30 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Column chromatography (SiO₂, 3:1 hexanes:acetone)provided 1,1-dimethylethyl(3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate which was used directly in the next step.MS (EI) for C₂₈H₃₁N₄O₄FClBr: 623 (MH⁺).

N-(4-Bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclo-penta[c]pyrrolo-5-ylmethyl]oxy}quinazolin-4-aminehydrochloride

1,1-Dimethylethyl(3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyl-oxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatederivative was taken up in methanol (50 mL) and treated with 4.0Mhydrogen chloride in dioxane (excess) and heated briefly to reflux.Concentration in vacuo gaveN-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-aminehydrochloride which was used directly in the next step. ¹H NMR (400 MHz,d₄-MeOH): 8.70 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H), 7.49 (t, 1H), 7.28(s, 1H), 4.25 (m, 2H), 4.08 (s, 3H), 3.57 (m, 1H), 3.02 (m, 4H),2.80-2.60 (m, 2H), 2.35 (m, 1H), 1.89 (m, 4H), 1.40 (m, 1). MS (EI) forC₂₃H₂₃N₄O₂FClBr: 522 (MH⁺).

N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

N-(4-Bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclo-penta-[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-aminehydrochloride was solubilized in formic acid (3.0 mL) and 37% aqueousformaldehyde (0.5 mL, 2.55 mmol) was added. The solution was heated to95° C. for 12 h and additional formaldehyde (1.0 mL, 5.10 mmol) wasadded. After heating an additional 12 h, the reaction mixture wasconcentrated in vacuo. The residue was taken up in methanol and treatedwith Bio-Rad AG 1-X8 resin hydroxide form until pH 8. The product wasfiltered, concentrated in vacuo, and purified by HPLC (reverse-phase,water/acetonitrile/0.1% TFA). Upon removal of solvent, the product wastaken up in methanol and treated with Bio-Rad AG 1-X8 resin hydroxideform until pH 8. The product was filtered and concentrated in vacuo thentaken up in fresh methanol and treated with 4.0 M hydrogen chloride indioxane (0.05 mL). Removal of solvent in vacuo provided 54.1 mg (24%) ofN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride. ¹H NMR (400 MHz, d₆-DMSO): 8.83 (d, 1H), 8.33 (s, 1H),7.80 (d, 1H), 7.56 (t, 1H), 7.40 (s, 1H), 4.16 (m, 2H), 4.01 (s, 3H),3.80-3.68 (m, 1H), 3.05 (m, 2H) 2.90-2.70 (m, 5H), 2.34 (m, 1H), 2.15(m, 2H), 1.75 (m, 1H), 1.57 (m, 2H), 1.35 (m, 1H). MS (EI) forC₂₄H₂₅N₄O₂FClBr: 537 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5r,6a)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 8.83 (d, 1H), 8.33 (s, 1H), 8.03 (d, 1H),7.93 (d, 1H), 7.41 (m, 1H), 4.16 (m, 2), 4.02 (s, 3H), 3.70 (m, 1H),3.05 (m, 2H), 2.91-2.75 (m, 5H), 2.34 (m, 1H), 2.16 (m, 2H), 1.75 (m,1H), 1.57 (m, 2H), 1.35 (m, 1H). MS (EI) for C₂₄H₂₅N₄O₂FClBr: 537 (MH⁺).

N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 8.81 (d, 1H), 8.39 (d, 1H), 7.61 (m, 1H),7.47 (m, 1H), 7.42 (s, 1H), 4.17 (m, 2H), 4.02 (s, 3H), 3.67 (m, 1H),3.05 (m, 2H), 2.91-2.75 (m, 5H), 2.34 (m, 1H), 216 (m, 2H), 1.75 (m,1H), 1.57 (m, 2H), 1.35 (m, 1H). MS (EI) for C₂₄H₂₅N₄O₂FCl: 475 (M⁺).

Example 14N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride 1,1-Dimethylethyl(3aR,6aS)-5-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxyl-ate

A solution of4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (0.22 g, 0.47 mmol), 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocvclopenta[c]pyrrole-2(1H)-carboxylate(0.16 g, 0.51 mmol), K₂CO₃ (0.33 g, 2.36 mmol) in N,N-dimethylacetamide(5 mL) was heated in a sealed reaction tube at 90° C. for 12 h. Thecrude reaction mixture was diluted with 100 mL 10% methanol in ethylacetate and washed with saturated aqueous sodium bicarbonate (1×30 mL),water (1×30 mL) and brine (1×30 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Columnchromatography (SiO₂, 3:2 hexanes:acetone) provided 1,1-dimethylethyl(3aR,6aS)-5-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta-[c]pyrrole-2(1H)-carboxylate which was used directlyin the next step. MS (EI) for C₂₈H₃₁Cl₂FN₄O₄: 577, 579 (MH⁺).

N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclo-penta[c]pyrrol-5-yl]methyl]oxy}quinazolin-4-aminehydrochloride

1,1-Dimethylethyl(3aR6aS)-5-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatewas taken up in methanol (10 mL) and treated with 4.0M hydrogen chloridein dioxane (excess) and heated briefly to reflux. Concentration in vacuoprovided.N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[[(3aR,5r,6aS)-octahydroyclopenta[c]pyrrol-5-yl]methy]oxy}quinazolin-4-aminehydrochloride. MS (EI) for 477, 479 (MH⁺).

N-(3,4-Dichloro-2-fluorophenyl)-7-({[3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

N-(3,4-Dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl]methyl]oxy}quinazolin-4-aminehydrochloride was solubilized in formic acid (5.0 mL) and 37% aqueousformaldehyde (1 mL) was added. The solution was heated to 95° C. for 12h. The reaction mixture was concentrated in vacuo. The residue was takenup in a mixture of 10% methanol in ethyl acetate (100 mL) and washedwith saturated aqueous sodium bicarbonate (2×30 mL) and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered thenconcentrated and purified by HPLC (reverse-phase,water/acetonitrile/0.1% TFA). Upon removal of solvent the product wastaken up in 10% methanol in ethyl acetate (100 mL) and washed withsaturated aqueous sodium bicarbonate (2×30 mL) and brine. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedthen taken up in methanol and treated with 4.0 M hydrogen chloride indioxane (1 eq.). Removal of solvent in vacuo provided 78.3 mg (25%) ofN-(3,4-dichloro-2-fluorophenyl)-7-({[(3a,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride. ¹H NMR (400 MHz, d₆-DMSO): 11.00 (bs, 1H), 8.36 (d, 1H),8.10 (s, 1H), 7.58 (s, 2H), 7.20 (d, 1H), 4.16 (m, 2H), 4.00 (s, 3H),3.35 (bs, 3H), 2.50 (m, 2H), 2.21 (m, 3H), 2.03 (m, 2H), 1.60 (m, 2H),1.12 (m, 2H). MS (EI) for C₂₄H₂₅Cl₂FN₄O₂: 491, 493 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 10.9 (bs, 1H), 8.46 (d, 1H), 8.10 (s, 1H),8.04 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 4.18 (m, 2H), 4.01 (s, 3H),3.33 (bs, 3H), 2.46 (m, 2H), 2.23 (s, 3H), 2.04 (m, 2H), 1.58 (m, 2H),1.14 (m, 2H). MS (EI) for C₂₄H₂₅Cl₂FN₄O₂: 491 (MH⁺).

N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 11.0 (bs, 1H), 8.60 (s, 1H), 8.14 (s, 1H),7.76 (d, 1H), 7.44 (t, 1H), 7.24 (s, 1H), 4.16 (m, 2H), 4.00 (s, 3H),3.35 (bs, 31H), 2.50 (m, 2H), 2.18 (m, 3H), 2.03 (m, 2H), 1.60 (m, 2H),1.12 (m, 2H). MS (EI) for C₂₄H₂₅BrCl₂N₄O₂: 550, 552 (MH⁺).

N-(3,4-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 10.98 (bs, 1H), 8.88 (s, 1H), 8.41 (s, 1H),8.20 (d, 1H), 7.86 (d, 1H), 7.75 (s, 1H), 7.46 (s, 1H), 4.08 (m, 2H),3.98 (s, 3H), 3.28 (m, 2H), 2.54 (m, 2H), 2.20 (s, m, 4H), 2.18 (m, 2H),1.62 (m, 2H), 1.24 (m, 2H). MS (EI) for C₂₄H₂₆Cl₂N₄O₂: 473 (MH⁺).

Example 15N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochlorideN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octa-hydro-cyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

A solution ofN-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclo-penta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-aminehydrobromide (0.1 g, 0.166 mmol), acetone (0.024 mL, 0.332 mmol), andglacial acetic acid (5 drops) in acetonitrile:water (3:1) was cooled to0° C. and sodium triacetoxyborohydride (53.0 mg, 0249 mmol) was added.The solution was warmed to room temperature and stirred 12 h. Additionalacetic acid (5 drops), acetone (0.30 mL, 6.54 mmol), sodiumtriacetoxyborohydride (0.300 g, 1.42 mmol) was added in portions over 12h. The acetonitrile was removed in vacuo and the aqueous layer wasdiluted with saturated aqueous sodium bicarbonate and 10% methanol inethyl acetate then the layers were separated. The aqueous layer wasextracted with 10% methanol in ethyl acetate (2×75 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated. Column chromatography (SiO₂, gradient of 30-50% methanolin chloroform) followed by concentration and treatment in methanol with4.0 M hydrogen chloride in dioxane (0.05 mL) and concentration providedN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride (75.7 mg, 76% yield). ¹H NMR (400 MHz, d₄-MeOH): 8.69 (s,1H), 7.97 (s, 1H), 7.67 (d, 1H), 7.50 (t, 1H), 7.28 (s, 1H), 4.27 (d,2H), 4.07 (s, 3H), 3.84-3.20 (m, 4H), 3.01 (m, 3H), 2.80 (m, 1H) 2.34(m, 3H), 1.52 (m, 2H), 1.42 (dd, 6-1); MS (EI) for C₂₆H₂₉N₄O₂FClBr: 565(MH⁺).

Using the same synthetic techniques and/or substituting with alternativereagents, the following compound of the invention was also prepared.

N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.68 (broad s, 1H), 7.98 (broad s, 1H), 7.54(m, 3H), 7.32 (broad s, 1H), 4.27 (d, 2H), 4.07 (s, 3H), 3.84-3.20 (m,4H), 3.01 (m, 3H), 2.80 (m, 1H) 2.34 (m, 3H), 1.93-1.75 (m, 2H), 1.42(dd, 6H); MS (EI) for C₂₆H₂₉N₄O₂FCl₂: 519 (MH⁺).

Example 16N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6a)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochlorideN-(4-Bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

A solution ofN-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclo-penta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-aminehydrobromide (0.1 g, 0.166 mmol) and acetaldehyde (0.010 mL, 0.249 mmol)in 50% methanol in tetrahydrofuran was cooled to 0° C. and sodiumcyanoborohydride (1 M in THF, 0.10 mL, 0.200 mmol) was added. Thesolution was warmed to room temperature and stirred for 1.5 h. Thesolvents were removed and the residue was partitioned between water and10% methanol in ethyl acetate. The layers were separated and the aqueouslayer was extracted with 10% methanol in ethyl acetate (3×50 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated. Column chromatography (SiO₂, gradient of5-10% methanol in chloroform), followed by treatment in methanol with4.0 M hydrogen chloride in dioxane (0.05 mL) and concentration providedN-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride (37.5 mg, 36% yield). 1H NMR (400 MHz,d₆-DMSO): 8.75 (d, 1H), 8.21 (broad s, 1H), 7.75 (d, 31H), 7.54 (t, 1H),7.34 (m, 1H), 7.12 (d, 11H), 4.16 (d, 2H), 4.00 (s, 3H), 3.75 (m, 1H),3.11-2.65 (m, 3H), 2.40 (m, 1H), 2.15 (m, 2H), 1.61 (m, 2H), 1.26 (m,5); MS (EI) for C₂₅H₂₇N₄O₂FClBr: 551 (MH⁺).

Using the same synthetic techniques and/or substituting with alternativereagents, the following compound of the invention were prepared:

N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2-methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 8.73 (d, 1H), 832 (broad s, 1H), 7.76 (d,1H), 7.54 (t, 1H), 7.41 (m, 1H), 7.22 (d, 1H), 4.18 (d, 2H), 4.01 (s,3H), 3.74 (m, 1H), 3.11 (m, 1H), 2.94 (m, 5H), 2.65 (m, 1H), 2.40 (m,1H), 2.13 (m, 2H), 2.00 (m, 1H), 1.69 (m, 1H), 1.36 (m, 1H), 0.98 (t,6H); MS (EI) for C₂₇H₃₁N₄O₂FClBr: 579 (MH⁺).

N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 8.77 (d, 1H), 8.36 (broad s, 1H), 7.63 (m,2H), 7.42 (m, 1H), 7.20 (d, 1H), 4.17 (d, 2H), 4.02 (s, 3H), 3.74 (m,1H), 3.11-2.75 (m, 4H), 2.66 (m, 1H), 2.36 (m, 1H), 2.14 (m, 2H), 1.80(m, 1H), 1.65 (m, 1H), 1.28 (m, 5H); MS (EI) for C₂₅H₂₇N₄O₂FCl₂: 505(MH⁺).

N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2-methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 8.83 (d, 1H), 8.36 (d, 1H), 7.68 (d, 1H),7.62 (t, 1H), 7.43 (d, 1H), 7.30 (d, 1H), 4.18 (d, 2H), 4.01 (s, 3H),3.75 (m, 1H), 3.11 (m, 1H), 2.95 (m, 5H), 2.67 (m, 1H), 2.40 (m, 1H),2.14 (m, 2H), 2.00 (m, 1H), 1.69 (m, 1H), 1.36 (m, 1H), 0.98 (t, 6H); MS(EI) for C₂₇H₃₁N₄O₂FCl₂: 533 (MH⁺).

Example 17 Ethyl(3aR,5r,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatehydrochloride Ethyl(3aR,5r,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatehydrochloride

A solution ofN-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-aminehydrobromide (0.050 g, 0.0830 mmol), triethylamine (0046 mL, 0.0332mmol) in 2.0 mL dichloromethane was cooled to 0° C. and ethylchloridocarbonate (0.010 mL, 0.0913 mmol) was added. The solution wasstirred for 0.5 h at low temperature and quenched with saturated aqueoussodium bicarbonate. The reaction mixture was then partitioned betweendichloromethane and saturated aqueous sodium bicarbonate. The layerswere separated and the aqueous layer was extracted with dichloromethane(2×75 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Column chromatography(SiO₂, 5% methanol in dichloromethane), followed by treatment inmethanol with 4.0 M hydrogen chloride in dioxane (0.05 mL) andconcentration provided ethyl (3aR,5r,6aS-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatehydrochloride (27.7 mg, 53% yield). ¹H NMR (400 MHz, d₄-MeOH): 8.59 (s,1H), 7.83 (s, 1H), 7.60 (d, 1H), 7.41 (t, 1H), 7.12 (s, 1H), 4.14 (d,2H), 4.11 (m, 2H), 4.09 (s, 3H), 3.45 (dd, 2H), 3.30 (dd, 2H), 2.67 (m,2H), 2.58 (m, 1H), 2.12 (m, 2H), 1.74 (m, 1H), 1.36 (m, 2H), 1.18 (t,3H); MS (EI) for C₂₆H₂₇N₄O₄FClBr: 595 (MH⁺).

Using the same synthetic techniques and/or substituting with alternativereagents, the following compound of the invention were prepared:

N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(methylsulfonyl)octahydrocycopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.70 (s, 1H), 7.94 (s, 1H), 7.69 (d, 1H),7.49 (t, 1H), 7.23 (s, 1H), 4.24 (d, 2H), 4.18 (m, 2H), 4.09 (s, 3H),3.45 (dd, 2H), 2.90 (s, 3H), 2.87 (m, 31H), 2.59 (m, 1H), 2.28 (m, 2H),1.43 (m, 2H); MS (EI) for C₂₄H₂₅N₄O₄FSClBr: 601 (MH⁺).

7-({[(3aR,5r,6aS)-2-acetyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.70 (s, 1H), 7.97 (s, 1H), 7.69 (d, 1H),7.49 (t, 1H), 7.28 (s, 1H), 4.14 (d, 2H), 4.25 (m, 2H), 4.08 (s, 3H),3.31 (m, 1H), 3.02 (m, 4H), 2.78 (m, 2H), 2.36 (m, 1H), 1.93 (m, 3H),1.43 (m, 2H); MS (EI) for C₂₅H₂₅N₄O₃FClBr: 565 (MH⁺).

Example 18N-(3,4-dichlorophenyl)-7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride 1,1-Dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c] pyrrole-2(1H)-carboxylate

Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of1,1-dimethylethyl (3aR,6aS)-5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.45 g, 2.00 mmol) in 10 mL methanol at 0° C.and the reaction mixture was stirred for 1 h at this temperature. Thesolvent was evaporated, the crude mixture was diluted with 100 mL ethylacetate and washed with water (30 mL), 1M aqueous hydrochloric acid andbrine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to give 1,1-dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c] pyrrole-2(1H)-carboxylate(0.44 g, 98%). ¹H NMR (400 MHz, d₆-DMSO): 4.08 (m, 1H), 3.40 (m, 2H),3.30 (m, 2H), 2.50 (m, 2H), 1.98 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). MS(EI) for C₁₂H₂₁NO₃: 228 (MH⁺).

1, 1-Dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclo-penta[c]pyrrole-2(1H)-carboxylate

Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to asolution of 1,1-dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 mLdichloromethane at 0° C. and the reaction mixture was stirred for 1 h atroom temperature. The solvent was evaporated, the resulting crudemixture was diluted with 100 mL ethyl acetate and washed with water (30mL), brine, 1M aqueous hydrochloric acid and brine again. The organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting crude 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatewas used without further purification. MS (EI) for C₁₃H₂₃NO₅S: 306(MH⁺).

1,1-dimethylethyl(3aR,6aS)-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy})hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (0.22 g, 0.49 mmol), 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.15 g, 0.45 mmol), potassium carbonate (0.34 g, 2.50 mmol) inN,N-dimethylacetamide (5 mL) was heated in a sealed reaction tube at 90°C. for 12 h. The crude reaction mixture was diluted with 100 mL 10%methanol in ethyl acetate and washed with saturated aqueous sodiumbicarbonate (1×30 mL), water (1×30 mL) and brine (1×30 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. Column chromatography (SiO₂, 3:2 hexanes:acetone) provided1,1-dimethylethyl(3aR,6a)-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy})hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.23 g, 98%). ¹H NMR (400 MHz, d₆-DMSO): 9.57 (s, 1H), 8.52 (s, 1H),8.24 (d, 1H), 7.88 (dd, 1H), 7.78 (s, 1H), 7.62 (d, 1H), 7.13 (s, 1H),5.15 (m, 1H), 3.96 (s, 3H), 3.42 (m, 2H), 3.36 (m, 2H), 2.80 (bs, 2H),2.06 (m, 2H), 1.94 (m, 2H), 1.40 (s, 9H). MS (EI) for C₂₇H₃₀Cl₂N₄O₄: 547(MH⁺).

N-(3,4-dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclo-penta[c]pyrrol-5-yl]oxy}quinazolin-4-aminehydrochloride: 1,1-Dimethylethyl(3aR,6aS)-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy})hexahydrocyclo-penta[c]pyrrole-2(1H)-carboxylate(0.23 g, 0.42 mmol) was taken up in methanol (10 mL) and treated with4.0M hydrogen chloride in dioxane (excess) and heated briefly to reflux.Concentration in vacuo providedN-(3,4-dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclo-penta[c]pyrrol-5-yl]oxy}quinazolin-4-amine hydrochloride (0.20 g, 100%). MS (EI) forC₂₂H₂₂Cl₂N₄O₂: 445 (MH⁺).

N-(3,4-Dichlorophenyl)-7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

N-(3,4-Dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta-[c]pyrrol-5-yl]oxy}quinazolin-4-aminehydrochloride (0.20 g, 0.42 mmol) was solubilized in formic acid (5.0mL) and 37% aqueous formaldehyde (1 mL) was added. The solution washeated to 95° C. for 12 h. The reaction mixture was concentrated invacuo. The residue was taken up in a mixture of 10% methanol in ethylacetate (100 mL) and washed with saturated aqueous sodium bicarbonate(2×30 mL) and brine. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by HPLC(reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solventthe product was taken up in a mixture of 10% methanol in ethyl acetate(100 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL)and brine. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated then the product was taken up in methanol andtreated with 4.0 M hydrogen chloride in dioxane (1 eq.). Removal ofsolvent in vacuo provided 116 mg (56%) ofN-(3,4-dichlorophenyl)-7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride. ¹H NMR (400 MHz, d₆-DMSO): 11.05 (bs, 1H), 8.90 (s, 1H),8.44 (s, 1H), 8.18 (d, 1H), 7.84 (dd, 1H), 7.76 (s, 1H), 7.48 (s, 1H),5.30 (m, 1H), 4.00 (s, 3H), 3.35 (m, 2H), 2.90 (m, 2H), 2.24 (m, 5H),2.10 (m, 2H), 1.24 (m, 2H). MS (EI) for C₂₃H₂₄Cl₂N₄O₂: 459, 461 (MH⁺).

Example 19N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride3-(Chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine

A solution of (3R)-morpholin-3-ylmethanol (4.21 g, 36.0 mmol) in2-(chloromethyl)oxirane (28.2 mL, 0.360 mol) was heated to 40° C. for 3h and then the solution was concentrated in vacuo. The intermediate wascooled in an ice bath and treated with 30.0 mL of concentrated sulfuricacid. The mixture was heated to 170° C. for 2 h and then allowed to coolto room temperature. The mixture was poured into ice-water and solidsodium bicarbonate was carefully added until the solution was basic. 10%methanol in ethyl acetate was added and the biphasic mixture wasfiltered. The layers were separated and the aqueous layer was extracted(3×100 mL 10% methanol in ethyl acetate). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. Column chromatography (SiO₂, 2:5 hexanes:ethyl acetate) provided3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine 2.44 g(35%) as two separated diastereomers.(3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine:(0.886 g, 13% yield): ¹H NMR (400 MHz, CDCl₃): 3.91 (m, 3H), 3.82 (m,1H), 3.68 (dt, 1H), 3.61 (dd, 1H), 3.47 (dd, 1H), 3.35 (t, 1H), 3.19 (t,1H), 2.80 (d, 1H), 2.54 (m, 2H), 2.40 (m, 2H); MS (EI) for C₈H₁₄NO₂Cl:192 (MH⁺).(3S,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine:(1.55 g, 22% yield): ¹H NMR (400 MHz, CDCl₃): 3.85 (m, 2H), 3.73 (m,3H), 3.50 (m, 2H), 3.29 (t, 1H), 3.18 (t, 1H), 2.85 (dd, 1H), 2.64 (dd,1H), 2.40 (m, 2H), 2.17 (t, 1H); MS (EI) for C₈H₁₄NO₂Cl: 192 (MH⁺).

Hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate

A suspension of(3R,9aS)-3-(chloromethyl)hexahydro-11H-[1,4]oxazino[3,4-c][1,4]oxazine(1.97 g, 10.3 mmol) and potassium acetate (10.1 g, 102 mmol) in DMF(20.0 mL) was stirred at 140° C. for 16 h, and then at 150° C. foranother 12 h. The reaction mixture was partitioned between water (250mL) and ethyl acetate (250 mL), the organic layer was washed with 5%lithium chloride (2×100 mL) and brine (100 mL) then dried over anhydroussodium sulfate and concentrated in vacuo. Column chromatography (SiO₂,1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded 0.92 g (42%)of hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate as ayellow oil. Distinct diastereomers as described above were converted inthis step to give:(3R,9aS)-hexahydro-1-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate:¹H NMR (400 MHz, CDCl₃): 4.18 (dd, 1H) 4.00 (m, 1H), 3.80 (dd, 1H), 3.68(dt, 1H), 3.60 (dd, 1H), 3.46 (m, 2H), 3.22 (t, 1H), 2.64 (dd, 1H), 2.53(m, 2H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), and(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate:¹H NMR (400 MHz, CDCl₃): 4.09 (d, 2H), 3.90-3.82 (m, 2H), 3.75-3.64 (m,3H), 3.27 (t, 1H), 3.18 (t, 1H), 2.69 (dd, 1H), 2.63 (m, 1H), 2.46-2.33(m, 2H), 2.16 (t, 1H), 2.10 (s, 3H).

(3R,9aS)-Hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethylmethanesulfonate

To a solution of(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate(0.922 g, 4.28 mmol) in methanol (14.0 mL) was added 1.03 mL (4.50 mmol)of sodium methoxide (25% wt. in methanol) dropwise at room temperature.After 5 min., 1.6 mL (6.43 mmol) of 4.0M hydrogen chloride in dioxanewas added and a pink precipitate formed. The solution was concentratedin vacuo and the pink solid was taken up in 30.0 mL dichloromethane.This slurry was cooled in an ice bath and triethylamine (3.0 mL, 21.5mmol) was added, followed by methanesulfonyl chloride (0.37 mL, 4.71mmol). The resultant yellow solution was stirred for 30 minutes at roomtemperature. The mixture was then partitioned between dichloromethaneand saturated aqueous sodium bicarbonate then the aqueous layer wasextracted (3×50 mL dichloromethane). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuoto provide crude(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethylmethanesulfonate which was taken on to the following reaction withoutpurification.

N-(4-Bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

A solution of(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethylmethanesulfonate (0.215 g, 0.856 mmol),4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-olhydrochloride (0.247 g, 0.570 mmol), and potassium carbonate (0.400 g,2.90 mmol) in DMF (1.9 mL) was heated in a sealed reaction tube at 75°C. for 12 h, then 90° C. for 12 h. The reaction mixture was concentratedin vacuo and the residue was partitioned between 10% methanol in ethylacetate and saturated aqueous sodium bicarbonate. The layers wereseparated and the aqueous layer was extracted (3×50 mL 10% methanol inethyl acetate). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude residuewas purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Uponremoval of solvent the product was taken up in methanol and treated withBio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product wasfiltered and concentrated in vacuo then taken up in methanol and treatedwith 4.0 M hydrogen chloride in dioxane (0.10 mL). Removal of solvent invacuo provided 32.1 mg (10%) ofN-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride. MS (EI) for C₂₃H₂₃N₄O₄FClBr: 554 (M⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(3,4-dichlorophenyl)-7-[(hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl)oxy]-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₆-DMSO): 8.90 (s, 1H), 8.50 (s, 1H), 8.19 (d, 1H),7.85 (d, 1H), 7.75 (d, 1H), 7.42 (s, 1H), 4.51 (m, 1H), 4.32 (m, 2H),4.04 (s, 3H), 4.00-3.62 (m, 4H); MS (EI) for C₂₃H₂₄N₄O₄Cl₂B: 491 (MH⁺).

N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.71 (s, 1H), 7.99 (s, 1H), 7.58-7.52 (m,2H), 7.33 (s, 1H), 4.50 (m, 1H), 4.44 (d, 2H), 4.17-3.94 (m, 4H), 4.09(s, 3H), 3.82-3.59 (m, 5H), 3.54-3.37 (m, 2H); MS (EI) forC₂₃H₂₃N₄O₄Cl₂F: 509 (MH⁺).

N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.71 (s, 1H), 7.99 (s, 1H), 7.69 (d, 1H),7.49 (t, 1H), 7.32 (s, 1H), 4.49 (m, 1H), 4.44 (m, 2H), 4.16-3.95 (m,4H), 4.10 (s, 3H), 3.82-3.58 (m, 5H), 3.54-3.35 (m, 2H); MS (EI) forC₂₃H₂₃N₄O₄BrClF: 553 (MH+).

N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

MS (EI) for C₂₃H₂₃N₄O₄ClF₂: 493 (MH⁺).

N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.73 (s, 1H), 7.99 (s, 1H), 7.86 (d, 1H),7.64 (d, 1H), 7.33 (s, 1H), 4.51 (n, 1H), 4.44 (d, 2H), 4.16-3.94 (m,4H), 4.10 (s, 3H), 3.84-3.60 (m, 5H), 3.54-3.36 (m, 2H); MS (ET) forC₂₃H₂₃N₄O₄ClF₂: 509 (MH⁺).

N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

1H NMR (400 MHz, d₄-MeOH): 8.73 (s, 1H), 7.98 (s, 1H), 7.85 (d, 1H),7.76 (d, 1H), 7.33 (s, 1H), 4.49 (m, 1H), 4.44 (d, 2H), 4.16-3.94 (m,4H), 4.09 (s, 3H), 3.82-3.60 (m, 5H), 3.53-3.35 (m, 2H); MS (EI) forC₂₃H₂₃N₄O₄BrClF: 553 (MH⁺).

N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,9aS)-hexahydro-H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.67 (s, 1H), 8.00 (s, 1H), 7.84 (d, 1H),7.48 (d, 1H), 7.34 (s, 1H), 4.51 (m, 1H), 4.44 (d, 2H), 4.09 (s, 3H),4.15-4.00 (m, 4H), 3.82-3.63 (m, 5H), 3.63-3.38 (m, 2H); MS (EI) forC₂₃H₂₃N₄O₄Cl₂Br: 570 (MH⁺).

N-(4-bromo-2,3-dichlorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

MS (EI) for C₂₃H₂₃N₄O₄Cl₂Br: 570 (MH⁺).

N-(3,4-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

MS (EI) for C₂₃H₂₃N₄O₄FCl₂: 509 (MH⁺).

N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

MS (EI) for C₂₃H₂₃N₄O₄FClBr: 554 (MH⁺).

N-(4,5-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.74 (s, 1H), 8.00 (s, 1H), 7.86 (d, 1H),7.64 (d, 1H), 7.35 (broad s, 1H), 4.51 (m, 2H), 4.44 (m, 1H), 4.25-3.95(m, 4H), 4.09 (s, 3H), 3.82-3.63 (m, 5H), 3.63-3.38 (m, 2H); MS (EI) forC₂₃H₂₃N₄O₄FCl₂: 509 (MH⁺).

N-(3-chloro-2,4-difluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

MS (EI) for C₂₃H₂₃N₄O₄F₂Cl: 493 (MH⁺).

Example 20N-(3,4-dichlorophenyl)-7-[(2-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}ethyl)oxy]-6-(methyloxy)quinazolin-4-amine7-[(2-Aminoethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride

A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (1.00 g, 2.15 mmol), 1,1-dimethylethyl(2-bromoethyl)carbamate (0.480 g, 2.15 mmol), and potassium carbonate(1.78 g, 12.9 mmol) in N,N-dimethylacetamide (2.2 mL) was heated to 100°C. for 2.5 h. An additional 0.23 g (103 mmol) of 1,1-dimethylethyl(2-bromoethyl)carbamate was added and the reaction mixture was furtherheated to 100° C. for a total of 7 h. The crude reaction mixture waspartitioned between water and ethyl acetate and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (3×100mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo. Column chromatography(SiO₂, 3:2 hexanes:acetone) gave N-Boc product, which was then taken upin methanol and treated with 4M hydrogen chloride in dioxane whileheating. Dilution with ethyl ether precipitated a pale yellow solid,which was collected by filtration and dried to give 0.761 g (94%) of7-[(2-aminoethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride. ¹H NMR (400 MHz, d₆-DMSO): 12.01 (s, 1H), 8.94 (s, 1H),8.67 (s, 1H), 8.35 (broad s, 2H), 8.21 (s, 1H), 7.90 (dd, 1H), 7.75 (d,1H), 7.53 (s, 1H), 4.43 (t, 2H), 4.08 (s, 3H), 3.36 (min 2H).

N-(3,4-Dichlorophenyl)-7-[(2-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}ethyl)oxy]-6-(methyloxy)quinazolin-4-amine

To a DMF solution (3.0 mL) of7-[(2-aminoethyl)oxy]-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride (56.8 mg, 0.137 mmol) at room temperature, was addedglacial acetic acid (3 drops),(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (49.0 mg, 0.137 mmol),and sodium triacetoxyborohydride (43.0 mg, 0.205 mmol). After stirringfor 12 h, additional (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one(50.0 mg, 0.140 mmol), acetic acid (3 drops) and sodiumtriacetoxyborohydride were added. The solution was quenched with water,filtered and purified by HPLC (reverse-phase, acetonitrile/water/0.1%TFA). Upon removal of solvent, the product was taken up in methanol andtreated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. Theproduct was filtered and concentrated in vacuo, to provide 45.1 mg (66%)ofN-(3,4-dichlorophenyl)-7-[(2-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}ethyl)oxy]-6-(methyloxy)quinazolin-4-amine.¹H NMR (400 MHz, d₆-DMSO): 9.63 (s, 1H), 8.55 (s, 1H), 8.26 (d, 1H),7.90 (dd, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.23 (d, 1H), 4.20 (t, 1H),4.15 (t, 3H), 3.97 (s, 1H), 3.03 (m, 1H), 2.91 (t, 2H), 2.81 (t, 1H),2.17 (s, 3H), 2.00-1.84 (min 6H), 1.67-1.32 (m, 4H): MS (EI) forC₂₅H₂₉N₅O₂Cl₂: 502 (MH⁺).

Example 21N-(3,4-dichlorophenyl)-7-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochlorideN-(3,4-Dichlorophenyl)-7-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

A solution of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (0.150 g, 0.322 mmol),(3-endo)-3-[(methylsulfonyl)oxy]-8-azabicyclo[3.2.1]octane (0.106 g,0.483 mmol), and potassium carbonate (0.220 g, 1.60 mmol) inN,N-dimethylacetamide (1.1 mL) was heated in a sealed tube at 100° C.for 12 h, followed by 48 h at room temperature. The crude reactionmixture was filtered through celite using methanol eluent, and thesolvents were removed in vacuo. The residue was purified by HPLC(reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent,the product was taken up in methanol and treated with Bio-Rad AG 1-X8resin (hydroxide form) until pH 8. The product was filtered andconcentrated in vacuo, then taken up in methanol and treated with 4.0 Mhydrogen chloride in dioxane (0.050 mL). Removal of solvent in vacuoprovided 48.7 mg (31%) ofN-(3,4-dichlorophenyl)-7-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride. ¹H NMR (400 MHz, d₆-DMSO): 10.69 (s, 1H), 8.92 (s, 1H),8.32 (s, 1H), 8.17 (d, 1H), 7.81 (m, 2H), 7.75 (d, 1H), 5.05 (m, 1H),4.02 (s, 3H), 2.69 (d, 2H), 2.39 (m, 1H) 2.29-2.18 (m, 6H); MS (EI) forC₂₃H₂₄N₄O₂Cl₂: 459 (MH⁺).

Example 22N-(3,4-dichlorophenyl)-7-({[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

7-{[(3-endo)-8-Azabicyclo[3.2.1]oct-3-ylmethyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride: A solution of4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (0.200 g, 0.429 mmol), 1,1-dimethylethyl(3-endo)-3-{[(methylsulfonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylate(0.200 g, 0.626 mmol), and potassium carbonate (0.300 g, 2.17 mmol) inN,N-dimethylacetamide (1.4 mL) was heated in a sealed tube at 110° C.for 12 h. Additional mesylate (0.430 g 1.35 mmol) was added and themixture was heated for 2 h at 110° C. The crude reaction mixture waspartitioned between 10% methanol in ethyl acetate (50 mL) and water (50mL). The layers were separated and the organic layer was washed withwater (2×50 mL) and IM aqueous sodium hydroxide (1×50 mL). The organiclayer was dried over anhydrous sodium sulfate and the solvent wasremoved in vacuo. The residue was purified by column chromatography(SiO₂, 2:1 hexanes:ethyl acetate), followed by HPLC (reverse-phase,acetnitrile/water/0.1% TFA). Solvent was removed in vacuo and theresidue partitioned with 10% methanol in ethyl acetate and water. Theaqueous layer was made basic with saturated aqueous sodium bicarbonate.The layers were separated and the aqueous layer was further extractedwith 10% methanol in ethyl acetate (2×). The combined organic extractswere dried over anhydrous sodium sulfate, filtered and the concentratedin vacuo. The residue was taken up in methanol and treated with 4.0 Mhydrogen chloride in dioxane then concentrated to provide7-{[(3-endo)-8-azabicyclo[3.2.1]oct-3-ylmethyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride (0.104 g, 53%). MS (EI) for C₂₃H₂₄N₄O₂Cl₂: 459 (MH⁺).

N-(3,4-Dichlorophenyl)-7-({[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

7-{[(3-Endo)-8-azabicyclo[3.2.1]oct-3-ylmethyl]oxy}-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride, (0.104 g, 0.210 mmol) was combined with 37% aqueousformaldehyde (0.10 mL, 1.26 mmol) in formic acid (1.0 mL) and thesolution was heated to 110° C. for 12 h. The solvent was removed invacuo and the residue was taken up in methanol and treated with Bio-RadAG 1-X8 resin (hydroxide form) until pH 8. The product was filtered andconcentrated in vacuo. The residue was purified by HPLC (reverse-phase,acetonitrile/water/0.1% TFA). Upon removal of solvent, the product wastaken up in methanol and treated with Bio-Rad AG 1-X8 resin (hydroxideform) until pH 8. The product was filtered and concentrated in vacua,then taken up in methanol and treated with 4.0 M hydrogen chloride indioxane (0.10 mL). Removal of solvent in vacuo provided 41.4 mg (39%) ofN-(3,4-dichlorophenyl)-7-({[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride. ¹H NMR (400 MHz, d₆-DMSO): 8.89 (s, 2H), 8.45 (s, 1H),8.20 (s, 1H), 7.86 (d, 1H), 7.75 (d, 1H), 7.46 (s, 1H), 4.24 (m, 2H),4.04 (s, 3H), 3.97 (broad s, 1H), 3.85 (broad s, 1H), 265 (d, 1H),2.25-2.51 (m, 6H), 2.03-1.80 (m, 5H); MS (EI) for C₂₄H₂₆N₄O₂Cl₂: 473(MH⁺).

Example 23N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-aminetrifluoroacetate(8aR)-6-(Chloromethyl)tetrahydro-H-[1,3]thiazolo[4,3-c][1,4]oxazine

A solution of (4R)-1,3-thiazolidin-4-ylmethanol (0.300 g, 2.52 mmol) in2-(chloromethyl)oxirane (2.0 mL, 25.5 mmol) was heated under nitrogen to40° C. for 12 h. The solution was then cooled to room temperature and2-(chloromethyl)oxirane was removed in vacuo. The crude intermediate wascooled in ice, and was taken up in 2.0 mL of concentrated sulfuric acid.The resulting mixture was heated to 200° C. for 0.5 h then pouredcarefully onto wet ice, which was allowed to melt. The aqueous solutionwas carefully made basic using solid sodium bicarbonate and theresulting mixture was filtered using water and 10% methanol in ethylacetate as eluent. The layers were separated and the aqueous layer wasextracted with 10% methanol in ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give 11.6 mg (2.4% yield) of crude(8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine asa mixture of diastereomers which was directly taken on to the next step.

N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-aminetrifluoroacetate

A solution of(8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine(11.6 mg, 0.0599 mmol),4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (30.0 mg, 0.0644 mmol), and potassium carbonate(45.0 mg, 0.326 mmol) in N,N-dimethylacetamide (1.0 mL) was heated in asealed tube to 150° C. for 12 h. The crude reaction mixture was directlypurified via reverse-phase preparative HPLC (acetonitrile/water/0.1%TFA). Lyophillization of the pure fractions yielded 3.5 mg (8.9%) ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin-4-aminetrifluoroacetate. ¹H NMR (400 MHz, d₆-DMSO): 8.80 (s, 1H), 8.11 (s, 1H),7.99 (s, 1H), 7.74 (s, 2H), 7.29 (s, 1H), 4.29 (d, 2H), 4.11 (m, 2H),4.00 (s, 3H), 3.96 (m, 1H), 2.99 (m, 2H), 2.56 (t, 1H), 2.367 (m, 1H);MS (EI) for C₂₂H₂₂N₄O₃SCl₂: 492 (MH⁺).

Example 24N-(3,4-dichlorophenyl)-7-({2-[(3-endo)-8-methyl-8-azabicyclo[13.2.1]oct-3-yl]ethyl}oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride

1,1-Dimethylethyl(3-endo)-3-{2-[(methylsulfonyl)oxy]ethyl}-8-azbicyclo[3.2.1]octane-8-carboxylate:To a solution of 1,1-dimethylethyl(3-endo)-3-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate(30.3 ing, 1.19 mmol) in dichloromethane (4.0 mL), was addedtriethylamine (0.5 mL, 3.56 mmol) and the solution was cooled to 0° C.under nitrogen. Methanesulfonyl chloride (0.11 mL, 1.42 mmol) was addedslowly and mixture was allowed to warm to room temperature and stirredfor 1 h. The reaction mixture was partitioned between dichloromethaneand water. The aqueous phase was extracted with dichloromethane (2×100mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to provide 35.1 mg (89%) of1,1-dimethylethyl(3-endo)-3-{2-[(methylsulfonyl)oxy]ethyl}-8-azabicyclo[3.2.1]octane-8-carboxylate,which was carried forward without purification.

1,1-Dimethylethyl(3-endo)-3-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of 1,1-dimethylethyl(3-endo)-3-{2-[(methylsulfonyl)oxy]ethyl}-8-azabicyclo[3.2.1]octane-8-carboxylate(0.175 g, 0.526 mmol) in N,N-dimethylacetamide (3.5 mL) was added4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-oltrifluoroacetate (salt) (0.490 g, 1.05 mmol) and potassium carbonate(0.728 g, 5.26 mmol), and the reaction was stirred at 110° C. for 18 h.An additional portion of 1,1-dimethylethyl(3-endo)-3-{2-[(methylsulfonyl)oxy]ethyl}-8-azabicyclo[3.2.1]octane-8-carboxylate(0.175 g, 0.526 mmol) was added and the mixture was stirred at 140° C.for 2 h. Another portion of the mesylate (0.300 g, 1.05 mmol) inN,N-dimethylacetamide (4.0 mL) was added and the mixture continued tostir at 140° C. for a further 18 h. The reaction mixture wasconcentrated in vacuo, and the residue was partitioned between 10%methanol in ethyl acetate and water. The organic layer was washed (3×50mL water) and the combined aqueous portions were extracted (2×100 mL 10%methanol in ethyl acetate). All organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by HPLC (reverse-phase, acetonitrile/water/0.1%TFA). Upon concentration the remaining aqueous layer was neutralizedwith solid sodium bicarbonate, extracted (100 mL 10% methanol in ethylacetate), dried over anhydrous sodium sulfate then filtered andconcentrated in vacuo to afford 1,1-dimethylethyl(3-endo)-3-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate(39.9 mg, 66% yield). ¹H-NMR (400 MHz; d₆-DMSO): 9.43 (broad s, 1H),8.48 (s, 1H), 7.87 (s, 1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.22 (d, 1H),7.02 (s, 1H), 4.23-3.82 (m, 4H), 380 (s, 3H), 2.19 (m 1H), 1.93 (s, 6H),1.69-1.42 (m, 3H), 1.36 (s, 9H), 1.22 (m 1H).

7-({2-[(3-endo)-8-Azabicyclo[3.2.1]oct-3-yl]ethyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-aminehydrochloride

1,1-Dimethylethyl(3-endo)-3-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylatewas solubilized in methanol (2.3 mL) and treated with 4.0 M hydrogenchloride in dioxane (2.3 mL). The solution was heated to reflux thenimmediately allowed to cool to room temperature. The solution was thenconcentrated in vacuo to give7-({2-[(3-endo)-8-azabicycio[3.2.1]oct-3-yl]ethyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine hydrochloride (34.6 mg, 98% yield). MS (EI) forC₂₄H₂₆Cl₂N₄O₂: 473 (MH⁺).

N-(3,4-Dichlorophenyl)-7-({2-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]ethyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

To a solution of7-({2-[(3-endo)-8-azabicyclo[3.2.1]oct-3-yl]ethyl}oxy)-N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine hydrochloride (0.346 g, 0.678 mmol) in formic acid(2.7 mL), was added aqueous formaldehyde (37%, 0.27 mL, 4.07 mmol) andthe mixture was heated to 110° C. for 5 h, then allowed to cool to roomtemperature. The solution was concentrated in vacuo and the residue wastaken up in methanol and treated with AG 1-X8 resin (hydroxide form) topH 8. The mixture was filtered and concentrated then the residuepurified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA) and thepure fractions lyophillized. The residue was taken up in methanol andneutralized with AG 1-X8 resin (hydroxide form) to pH 8 then filteredand concentrated. The residue was taken into methanol (3 mL) and treatedwith 4.0 M hydrogen chloride in dioxane to pH 2. Concentration in vacuoafforded the title compoundN-(3,4-dichlorophenyl)-7-({2-[(3-endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl]ethyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride (12.5 mg, 36% yield), ¹H NMR (400 MHz; d₆-DMSO): 8.86 (s,2H), 8.40 (s, 1H), 8.16 (t, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.38 (s,1H), 4.22 (m, 2H), 4.03 (s, 3H), 3.92 (broad s, 2H), 2.28 (m, 2H),2.12-1.91 (m, 6H) 0, 1.88-1.58 (m, 6H); MS (EI) for C₂₅H₂₈Cl₂N₄O₂: 485(MH⁺).

Example 251,4:3,6-Dianhydro-5-O-{4-[(3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl}-2-deoxy-2-fluoro-L-iditol

1,4:3,6-dianhydro-2-O-[4-(methyloxy)carbonyl-2-(methyloxy)phenyl]-5-O-(methylsulfonyl)-D-glucitol:1,4:3,6-dianhydro-2,5-bis-O-(methylsulfonyl)-D-mannitol (15.6 g, 51.7mmol) and methyl vanillate (9.40 g, 51.7 mmol) were dissolved in DMF (60mL) and cesium carbonate (33.7 g, 103 mmol) was added. The mixture wasstirred at 100° C. for 2.5 h then cooled to room temperature andfiltered. The filtrate was concentrated in vacuo and the residue waspartitioned between ethyl acetate and water. Hexanes were added to thebiphasic mixture and the precipitate was removed by filtration anddiscarded. From the filtrate a second crop of precipitate was obtained(8.7 g) and the material was purified by silica gel columnchromatography using 30% ethyl acetate in chloroform eluent to afford1,4:3,6-dianhydro-2-O-[4-(methyloxy)carbonyl-2-(methyloxy)phenyl]-5-O-(methylsulfonyl)-D-glucitolas a colorless solid (3.08 g, 15% yield). ¹H-NMR (400 MHz, CDCl₃): 7.65(dd, 1H), 7.57 (d, 1H), 6.95 (d, 1H), 5.12 (q, 1H), 4.95 (t, 1H),4.93-4.90 (m, 1H), 4.67 (d, 1H), 4.28-4.23 (m, 1H), 4.19 (dd, 1H), 4.03(dd, 1H), 3.95 (dd, 1H), 3.90 (2×s, 6H), 3.15 (s, 3H).

1,4:3,6-dianhydro-2-O-[4-(methyloxy)carbonyl-2-(methyloxy)phenyl]-5-O-(methylsulfonyl)-D-glucitol(4.38 g, 11.3 mmol) was taken into methyl sulfoxide (30 mL) followed byaddition of potassium fluoride (7.5 g, 128 mmol) and the mixture washeated to 180° C. over 12 hours. The mixture was cooled to roomtemperature and partitioned with ethyl acetate and water. The organiclayer was washed with water (3×) then brine and dried over anhydrousmagnesium sulfate. Filtration and concentration of the organic solutionfollowed by further purification by silica gel column chromatographyusing hexanes:ethyl acetate (2:1) eluent afforded1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl}-L-iditol(1.5 g, 43% yield) as a colorless oil which was employed in the nextstep without further purification. GCMS: Calculated for C₁₅H₁₇O₆F: 312(M⁺).

1,4:3,6-Dianhydro-2-deoxy-2-fluoro-5-O-{2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl}-L-iditol(4.8 g, 15.4 mmol) was taken into dichloromethane (45 mL) and thesolution cooled to 0° C. Fuming nitric acid (90% reagent, 1.3 mL) wasadded dropwise to the solution followed by addition of concentratedsulfuric acid (0.3 mL). Two additional aliquots of both acids were addedat ten minute intervals and the mixture was allowed to warm to roomtemperature with stirring an additional 20 minutes. An excess of ethylacetate (100 mL) was added to the mixture followed by water (50 mL) andthe organic layer subsequently washed with water (1×), saturated aqueoussodium bicarbonate (2×) and brine then dried over anhydrous magnesiumsulfate, filtered and concentrated to give1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{2-(methyloxy)-4-[(methyloxy)carbonyl]-5-nitrophenyl}-L-iditol(5.0 g, 91% yield) as a yellow amorphous residue. The material washydrogenated at 50 psi hydrogen gas pressure in a Parr apparatus inmethanol solution (50 mL) using 10% Pd/C catalyst (1.0 g) over 12 hours.Filtration of the catalyst and concentration of the organic solutionafforded5-O-{5-amino-2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl}-1,4:3,6-dianhydro-2-deoxy-2-fluoro-L-iditol(4.5 g, 90% overall yield) as a solid. ¹H-NMR (400 MHz, CDCl₃): 7.32 (s,1H), 6.24 (s, 1H), 5.55-5.62 (br s, 2H), 5.10 (dd, 1H), 4.82 (d, 2H),4.79 (m, 1H), 4.81-4.03 (m, 4H), 3.93 (dd, 1H), 3.85 (s, 3H), 3.78 (s,3H). MS (EI) for C₁₅H₁₈NO₆F: 328 (MH⁺).

5-O-{5-Amino-2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl}-1,4:3,6-dianhydro-2-deoxy-2-fluoro-L-iditol(4.5 g 13.7 mmol.) was taken into formamide (40 mL) followed by additionof ammonium formate (1.7 g, 27.5 mmol.) and the mixture was heated to165° C. for 2.5 hours. The mixture was then cooled to room temperatureand partitioned with ethyl acetate:hexanes (1:1) and water to give abiphasic suspension. The residue was collected by filtration, washedwith water then ethyl ether and dried in vacuo to give1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[6-(methyloxy)-4-oxo-3,4-dihydroquinazolin-7-yl]-L-iditol(3.61 g, 82% yield) as a tan solid. MS (EI) for C₁₅H₁₅N₂O₅F: 323 (MH⁺).

1,4:3,6-Dianhydro-2-dofluoro-5-O-[6-(methyloxy)-4-oxo-3,4-dihydroquinazolin-7-yl]-L-iditol(3.61 g, 11.2 mmol.) was suspended in chloroform (50 mL) followed byaddition of DMF (1.0 mL) and oxalyl chloride (2.0 mL) then the mixturewas brought to reflux for 10 minutes then cooled followed by addition ofDMF (0.5 mL) and oxalyl chloride (1.0 mL) and the mixture was brought toreflux an additional hour. The mixture was again allowed to cool to roomtemperature and neutralized by slow addition of saturated aqueous sodiumbicarbonate. The mixture was extracted with chloroform (2×) then ethylacetate (1×) and the combined organic layers were dried over anhydrousmagnesium sulfate, filtered and concentrated to give1,4:3,6-dianhydro-5-O-[4-chloro-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-L-iditol(3.34 g, 88% yield). ¹H-NMR (400 MHz, d₆-DMSO): 8.91 (s, 1H), 7.57 (s,1H), 7.45 (s, 1H), 5.24 (dd, 1H), 5.24 (br s, 1H), 4.84-4.79 (m, 2H),4.17-3.87 (m, 4H), 4.01 (s, 3H). MS (EI) for C₁₅H₁₄N₂O₄FCl: 341 (MH⁺).

1,4:3,6-Dianhydro-5-O-[4-chloro-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-L-iditol(3.34 g, 9.8 mmol.) and 3-chloro-2-fluoroaniline hydrochloride (2.0 g,10.8 mmol.) were taken into acetonitrile (50 mL) and the mixture wasbrought to reflux for 2.5 hours. The resulting suspension was cooled toroom temperature and diluted with an excess of ethyl ether. The solidproduct was collected by filtration and recrystallized from a minimum ofwarm methanol with addition of ethyl ether. The solid was collected byfiltration and dried in vacuo to give1,4:3,6-dianhydro-5-O-{4-[(3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl}-2-deoxy-2-fluoro-L-iditol(4.2 g, 95% yield) as an off white solid. ¹H-NMR (400 MHz, d₆-DMSO):12.11 (s, 1H), 8.84 (s, 1H), 8.52 (s, 1H), 7.64 (tr, 1H), 7.53 (tr, 1H),7.50 (s, 1H), 7.35 (tr, 1H), 5.24 (dd, 1H), 5.11 (tr, 1H), 4.16-3.89 (m,4H), 4.02 (s, 3H). MS (EI) for C₂₁H₁₈N₃O₄F₂Cl: 450 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention canbe prepared:

-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,3-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4-trifluorophenyl)    amino]quinazolin-7-yl}-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(2-chloro-4-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(2-bromo-4-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,6-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(3-chloro-4-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-chlorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-bromo-5-chloro-2-fluorophenyl)amino]-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,5-trifluorophenyl)    amino]quinazolin-7-yl}-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,4,6-trifluorophenyl)    amino]quinazolin-7-yl}-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}amino)-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2,3-dichlorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chloro-5-fluorophenyl)amino]-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(4,5-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(2,3,4-trichloro-phenyl)amino]quinazolin-7-yl}-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-{6-(methyloxy)-4-[(3,4,5-trichloro-phenyl)amino]quinazolin-7-yl}-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-bromo-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-methylphenyl)amino]-6-(methloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(2-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(2-fluorophenyl)amino]-6-(methyl-oxy)quinazol    in-7-yl]-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(3-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-[(4-fluorophenyl)amino]-6-(methyl-oxy)quinazolin-7-yl]-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(4-chlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,4-dichlorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(2,5-dichlorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(2-bromo-4,6-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[2-fluoro-3-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[2-bromo-5-(trifluoromethyl)phenyl]amino}-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[2-bromo-4-(trifluoromethyl)phenyl]amino}-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[3-bromo-5-(trifluoromethyl)phenyl]amino}-6-(methyl-oxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(2-bromophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol:    ¹H NMR (400 MHz, d₆-DMSO).-   1,4:3,6-dianhydro-5-O-[4-[(3-bromophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol:    ¹H NMR (400 MHz, d₆-DMSO).-   1,4:3,6-dianhydro-5-O-[4-[(4-bromophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol:    ¹H NMR (400 MHz, d₆-DMSO).-   1,4:3,6-dianhydro-5-O-[4-[(3-bromo-4-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(5-chloro-2-methylphenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-2-deoxy-5-O-[4-[(3,5-dimethylphenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[2,5-bis(methyloxy)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[5-chloro-2,4-bis(methyloxy)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-{[4-chloro-2,5-bis(methyloxy)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.-   1,4:3,6-dianhydro-5-O-[4-[(3-chloro-2,4-difluorophenyl)amino]-6-(methyloxy)    quinazolin-7-yl]-2-deoxy-2-fluoro-D-iditol.

Example 26N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine

A solution of 2-(chloromethyl)-4-(phenylmethyl)morpholine (498 mg, 2.21mmol) in methanol (20 mL) was hydrogenated over 10% Pd—C (120 mg) for 17h. The catalyst was filtered off, and the filtrate was concentrated togive 2-(chloromethyl)morpholine as a colorless oil. To a solution ofthis oil in methanol (20 mL) was added di-tert-butyl dicarbonate (425mg, 1.95 mmol), and the reaction mixture was stirred at room temperaturefor 5 h. Concentration and purification by column chromatography onsilica (9:1 hexanes/ethyl acetate) provided 1,1-dimethylethyl2-(chloromethyl)morpholine-2-carboxylate 283 mg (54%) as a colorlesssolid. ¹H NMR (400 MHz, d₄-MeOH): 4.02 (d, 1H), 3.88 (d, 1H), 3.81 (m,1H), 3.61-3.47 (m, 4-), 2.95 (br. s, 1H), 2.75 (br. s, 1H), 1.46 (s,9H).

To a solution of4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (12.95 g,38.52 mmol) in dimethylacetamide (80 mL) was added 1,1-dimethylethyl2-(chloromethyl)morpholine-2-carboxylate (11.94 g, 50.66 mmol) andpotassium carbonate (15.97 g, 115.55 mmol), and the reaction mixture wasstirred at 130° C. under nitrogen for 13 h. After cooling to roomtemperature, the mixture was partitioned between water (500 mL) andethyl acetate (250 mL). The layers were separated, the organic layerdiluted with hexanes (250 mL) and washed with water (200 mL). Thecombined aqueous layers were further extracted with ethyl acetate (2×200mL). Some product precipitated from the combined organic layers and wasfiltered. The solid was washed with methanol (2×50 mL) and dried to give4.77 g (25%) of 1,1-dimethylethyl2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}morpholine-4-carboxylateas a tan solid. The methanol washes were concentrated, combined with thefiltrate, washed with 5% lithium chloride (2×200 mL) and brine (200 mL),dried over sodium sulfate and concentrated. Crystallization frommethanol gave another 6.86 g (36%). ¹H NMR (400 MHz, d₄-MeOH): 8.47 (s,1H), 8.15 (d, 1H), 7.74 (dd, 1H), 7.70 (s, 1H), 7.49 (d, 1H), 7.15 (s,1-1H), 4.24-4.06 (m, 3H), 4.02 (s, 3H), 3.98-3.82 (m, 3H), 3.59 (m, 1H),3.00 (br. s, 2H), 1.48 (s, 9H); MS (EI) for C₂₅H₂₈N₄O₅Cl₂: 535 (MH⁺).

To a suspension of 1,1-dimethylethyl2-({[4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-yl]oxy}morpholine-4-carboxylate(4.77 g, 8.91 mmol) in methanol (50 mL) was added a 4M solution of HClin 1,4-dioxane (50 mL), and the reaction mixture was refluxed for 5 min.After cooling to room temperature, diethyl ether (100 mL) was added andthe precipitate was filtered and dried. The solid was dissolved inmethanol (200 mL) and treated with Bio-Rad 1-X8 resin hydroxide formuntil pH 8. Filtration and concentration in vacuo provided 3.32 g (86°%) ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amineas a brown solid. ¹H NMR (400 MHz, d₄-MeOH): 8.47 (s, 1H), 8.14 (d, 1H),7.73 (m, 2H), 7.49 (d, 1H), 7.15 (s, 1H), 4.24-4.13 (m, 2H), 4.09-3.97(m, 5H), 3.76 (m, 1H), 3.22 (dd, 1H), 3.02-2.90 (m, 3H); MS (EI) forC₂₀H₂₀N₄O₃Cl₂: 435 (MH⁺).

To a solution ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine(3.32 g, 7.7 mmol) in formic acid (33.2 mL) was added a 37 wt % solutionof formaldehyde in water (3.32 mL), and the reaction mixture was heatedat 95° C. for 2.5 h. After cooling to room temperature, the reactionmixture was concentrated. The residue was dissolved in methanol andtreated with Bio-Rad AG®1-X8 hydroxide form resin until pH 8. Filtrationand concentration in vacuo afforded 3.11 g (91%) of the title compoundas a yellow-brown solid. ¹H NMR (400 MHz, d₄-MeOH): 8.46 (s, 1H), 8.14(d, 1H), 7.73 (dd, 1H), 7.68 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H),4.21-4.09 (m, 2H), 4.02 (s, 3H), 4.01-3.91 (m, 3H), 2.96 (m, 1H), 2.75(m, 1H), 2.35 (s, 3H), 2.22 (m, 1H), 2.11 (t, 1H); MS (EI) forC₂₁H₂₂N₄O₃Cl₂: 449 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(phenylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine

¹H NMR (400 MHz, d₄-MeOH): 8.48 (s, 1H), 8.15 (d, 1H), 7.74 (m, 2H),7.50 (d, 1H), 7.38-7.24 (m, 5H), 7.16 (s, 1H), 4.21-4.09 (m, 2H),4.06-3.99 (m, 4H), 3.91 (m, 1H), 3.72 (m, 1H), 3.58 (s, 2H), 2.296 (m,1H), 2.73 (m, 1H), 2.25 (m, 1H), 2.16 (t, 1H); MS (ET) forC₂₇H₂₆N₄O₃Cl₂: 525 (MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,4-oxazepan-2-ylmethyl)oxy]quinazolin-4-amine

¹H NMR (400 MHz, d₄-MeOH): 8.47 (s, 1H), 8.14 (d, 1H), 7.73 (m, 2H),7.49 (d, 1H), 7.15 (s, 1H), 4.20-4.00 (m, 7H), 3.80 (m, 1H), 3.21 (dd,1H), 2.95 (m, 3H), 1.91 (m, 2H); MS (EI) for C₂₂H₂₄N₄O₃Cl₂: 449 (MH⁺).

N-(3,4-dichlorophenyl)-7-{[(4-methyl-1,4-oxazepan-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine

¹H NMR (400 MHz, d₄-MeOH): 8.46 (s, 1H), 8.14 (d, 1H), 7.73 (dd, 1H),7.70 (s, 1H), 7.49 (d, 1H), 7.14 (s, 1H), 4.23-4.13 (m, 2H), 4.09-3.93(m, 5H), 3.87 (m, 1H), 3.08 (d, 1H), 2.88 (m, 1H), 2.65 (m, 2H), 2.46(s, 3H), 2.05 (m, 1H), 1.92 (m, 1H); MS (EI) for C₂₂H₂₄N₄O₃Cl₂: 463(MH⁺).

N-(3,4-dichlorophenyl)-7-{[(4-ethyl-1,4-oxazepan-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz, d₄-MeOH): 8.77 (s, 1H), 8.06-8.05 (m, 2H), 7.72 (dd,1H), 7.60 (d, 1H), 7.31 (s, 1H), 4.62-4.32 (m, 3H), 4.30 (s, 3H),4.04-3.36 (m, 8H), 2.40-2.08 (m, 2H), 1.45 (tr, 3H); MS (EI) forC₂₃H₂₆N₄O₃Cl₂: 477 (MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(tetrahydro-2H-pyran-2-ylmethyl)oxy]quinazolin-4-amine:11-NMR (400 MHz, d₆-DMSO): 9.55 (s, 1H), 8.51 (s, 1H), 8.24 (d, 1H),7.88 (dd, 1H), 7.77 (s, 1H), 7.61 (d, 1H), 7.17 (s, 1H), 405 (m, 2H),3.97 (s, 3H), 3.92-3.88 (m, 1H), 3.73-3.65 (m, 1H), 3.42-3.38 (m, 2H),1.88-1.81 (m, 1H), 1.70-1.64 (m, 1H), 1.53-1.35 (m, 31-1); MS (EI) forC₂₁H₂₀N₃O₃Cl₂: 434 (MH⁺).

Example 27N-(3,4-dichlorophenyl)-7-[({2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine

(Dimethylamino)acetonitrile (1.16 mL, 11.9 mmol) was added to a mixtureof DMF (5 mL) and triethylamine (2 mL). Hydrogen sulfide gas was bubbledinto the solution until the solution was dark green. The solution wasthen heated at 70° C. for 0.5 h. Excess hydrogen sulfide was removedfrom the system by bubbling nitrogen into the solution and then thevolatiles were removed in vacuo. to afford2-(dimethylamino)ethanethioamide as burgundy crystals (0.660 g, 5.59mmol, 47% yield). ¹H NMR (400 MHz; CDCl₃): 2.30 (s, 6H); 3.37 (s, 2H;780 (br s, 1H); 8.80 (br s, 1H); GCMS for C₄H₁₀N₂S: 118 (M⁺).

2-(Dimethylamino)ethanethioamide (0.382 g, 3.24 mmol),1,3-dichloroacetone (0.453 g, 3.56 mmol) and sodium bicarbonate (0.301g, 3.56 mmol) was stirred in 1,2-dichloroethane (4 mL) at roomtemperature for 24 h. The reaction mixture was filtered and the filtercake was washed with 1,2-dichloroethane. The filtrate was added dropwiseto a cooled (ice bath) solution of thionyl chloride (0.260 mL, 3.56mmol) in 1,2-dichloroethane (2 mL). The solution was stirred at 70° C.for 0.5 h and then cooled to room temperature. The brown mixture wasfiltered and washed with 1,2-dichloroethane to affordN-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylaminehydrochloride as a brown solid (0.550 g, 2.42 mmol, 75% yield). ¹H NMR(400 MHz; D₂O): 2.79 (s, 61H); 4.52 (s, 2H); 4.61 (s, 2H); 7.60 (s, 1H).

N-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylaminehydrochloride hydrochloride (0.050 g, 0.220 mmol) and4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.074 g, 0.220mmol) were suspended in DMF (4 mL) and potassium carbonate (0.152 g,1.10 mmol) was added. The mixture was stirred at room temperature for 50h and then at 70° C. for 3.5 h. An additional portion ofN—{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylaminehydrochloride hydrochloride (0.019 g, 0.084 mmol) was added and themixture was stirred at 70° C. for a further 25 h. The reaction mixturewas concentrated in vacuo. and the residue was partitioned between ethylacetate and brine. The organic portion was washed with 1 N aqueoussodium hydroxide, brine, dried over sodium sulfate, filtered andconcentrated in vacuo. to afford a brown solid. Recrystallization fromethyl acetate/diethyl ether afforded the title compound as a pale brownsolid (0.016 g, 0.033 mmol, 15% yield). ¹H NMR (400 MHz; CDCl₃): 2.37(s, 6H); 3.79 (s, 2H); 4.00 (s, 3H); 5.34 (s, 2H); 7.00 (s, 1H); 7.15(br s, 1H); 7.34-7.37 (m, 2H); 7.55 (d, 1H); 7.57 (d, 1H); 7.96 (d, 1H);8.66 (s, 1H); MS (EI) for C₂₂H₂₁Cl₂N₅O₂S: 490 (MH⁺).

Example 28N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(morpholin-4-ylmethyl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine

Morpholin-4-ylacetonitrile (1.03 g, 8.17 mmol) was added to a mixture ofDMF (3.5 mL) and triethylamine (1.4 mL). Hydrogen sulfide gas wasbubbled into the solution until the solution was light green. Thesolution was then heated at 70° C. for 05 h. Excess hydrogen sulfide wasremoved from the system by bubbling nitrogen into the solution and thenthe volatiles were removed in vacuo to afford brown crystals. Thesecrystals were triturated with ethanol to afford2-morpholin-4-ylethanethioamide as very pale brown crystals (0.525 g,3.28 mmol, 40% yield). ¹H NMR (400 MHz; CDCl₃): 2.53-2.58 (m, 4H); 3.44(s, 2H); 3.70-3.74 (m, 4H); 7.74 (br s, 1H); 8.70 (br s, 1H); GCMS forC₆H₁₂N₂OS: 160 (M⁺).

2-Morpholin-4-ylethanethioamide (0.403 g, 2.52 mmol),1,3-dichloroacetone (0.353 g, 2.77 mmol) and sodium bicarbonate (0.234g, 2.77 mmol) was stirred in 1,2-dichloroethane (4 mL) at roomtemperature for 74 h at which point 1,4-dioxane was added in an attemptto improve solubility and the mixture was stirred for a further 30 h.The reaction mixture was filtered and the filter cake was washed with1,2-dichloroethane. The filtrate was added dropwise to a cooled (icebath) solution of thionyl chloride (0.202 mL, 2.77 mmol) in1,2-dichloroethane (3 mL). The solution was stirred at 70° C. for 0.5 hand then cooled to room temperature. The brown mixture was filtered andwashed with 1,2-dichloroethane to afford4-{[4-(chloromethyl)-,3-thiazol-2-yl]methyl}morpholine hydrochloride asa very pale brown solid (0.024 g, 0.091 mmol, 4% yield). ¹H NMR (400MHz; D₂O): 3.29-3.39 (m, 4H); 3.78-3.92 (m, 4H); 4.63 (s, 2H); 4.67 (s,2H); 7.67 (s, 1H); MS (EI) for C₉H₁₃ClN₂OS: 233 (MH⁺).

4-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}morpholine hydrochloride(0.024 g, 0.089 mmol) and4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (0.030 g,0.089 mmol) were suspended in DMF (2 mL) and potassium carbonate (0.062g, 0.449 mmol) was added. The mixture was stirred at 70° C. for 21 h.The reaction mixture was concentrated in vacuo and the residue waspurified by reverse phase HPLC to afford the title compound as acolorless solid (0.026 g, 0.049 mmol, 54% yield). ¹H NMR (400 MHz;CDCl₃): 2.50 (br s, 1H); 2.57-2.64 (m, 4H); 3.75 (t, 4H); 3.84 (s, 2H);3.96 (s, 3H); 5.28 (s, 2H); 7.09 (s, 1H); 7.31 (s, 1H); 7.37 (s, 1H);7.43 (d, 1H); 7.60 (dd, 1H); 7.97 (d, 1H); 8.61 (s, 1H); MS (EI) forC₂₄H₂₃Cl₂N₅O₃S: 532 (MH⁺).

Example 29N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine

(4-Methylpiperazin-1-yl)acetonitrile (1.03 g, 7.42 mmol) was added to amixture of DMF (5 mL) and triethylamine (2 mL). Hydrogen sulfide gas wasbubbled into the solution until the solution was dark green. Thesolution was then heated at 70° C. for 1 h. Excess hydrogen sulfide wasremoved from the system by bubbling nitrogen into the solution and thenthe volatiles were removed in vacuo to afford brown crystals. Thesecrystals were triturated with ethanol to afford2-(4-methylpiperazin-1-yl)ethanethioamide as very pale brown crystals(0.455 g, 2.63 mmol, 35% yield). ¹H NMR (400 MHz; CDCl₃): 2.29 (s, 3H);2.38-2.66 (m, 8H); 3.44 (s, 2H); 7.72 (br s, 1H); 8.76 (br s, 1H); GCMSfor C₇H₁₅N₃S: 173 (M⁺).

2-(4-Methylpiperazin-1-yl)ethanethioamide (0.438 g, 2.53 mmol),1,3-dichloroacetone (0.355 g, 2.78 mmol) and sodium bicarbonate (0.236g, 2.78 mmol) was stirred in chloroform (4 mL) at room temperature for48 h. The reaction mixture was filtered and the filter cake was washedwith chloroform. The filtrate was added dropwise to a cooled (ice bath)solution of thionyl chloride (0.205 mL, 2.78 mmol) in chloroform (2 mL).The solution was stirred at 60° C. for 0.5 h and then cooled to roomtemperature. The brown mixture was filtered and washed with chloroformto afford1-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-4-methylpiperazinehydrochloride as a brown solid (0.421 g, 1.49 mmol, 59% yield). ¹H NMR(400 MHz; D₂O): 2.89 (s, 3H); 3.18-3.43 (m, 4H); 3.56-3.78 (m, 4H); 4.56(s, 2H); 4.67 (s, 2H); 7.66 (s, 1H); MS (EI) for C₁₀H₁₆ClN₃S: 246 (MH⁺).

1-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-4-methylpiperazinehydrochloride (0.067 g, 0.238 mmol) and4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.080 g, 0.238mmol) were suspended in DMF (4 mL) and potassium carbonate (0.164 g,1.19 mmol) was added. The mixture was stirred at 70° C. for 21 h. Thereaction mixture was concentrated in vacuo and the residue was purifiedby reverse phase HPLC to afford the title compound as a colorless solid(0.025 g, 0.046 mmol, 19% yield). ¹H NMR (400 MHz; CDCl₃): 2.08 (s, 5H);2.39 (s, 3H); 2.59-2.74 (m, 6H); 3.44-3.78 (m, 5H); 3.86 (s, 2H); 3.98(s, 3H); 5.30 (s, 2H); 7.10 (s, 1H); 7.33 (s, 1H); 7.37 (s, 1H); 7.43(d, 1H): 7.61 (dd, 1H); 7.99 (d, 1H); 8.60 (s, 1H); MS (EI) forC₂₅H₂₆Cl₂N₆O₂S: 545 (MH⁺).

Example 30N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)-12,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine(Method 1)

Bromoacetonitrile (2.1 ml, 30.1 mmol) was added to a mixture of4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (10.12 g;30.1 mmol) and potassium carbonate (16.6 g; 120.1 mmol) in DMF (200nil). The mixture was stirred at room temperature overnight. The solventwas removed under high vacuum and the residue was triturated with water,filtered, washed with a mixture of hexane and ether (1/1) and driedunder vacuum to give{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetonitrile(9.6 g; 91% yield). ¹H NMR (400 MHz; DMSO-d₆): 3.99 (s, 3H), 5.40 (s,2H), 7.41 (s, 1H), 7.64 (d, 1H), 7.87 (dd, 1H), 7.90 (s, 1H), 8.23 (d,1H), 8.57 (s, 1H), 9.69 (s, 1H); MS (EI) for C₁₇H₁₂Cl₂N₄O₂: 375.06(MH⁺).

To a suspension of{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetonitrile(14.7 g; 39.3 mmol) in EtOH (600 ml) was added a 50% aqueous solution ofNH₂OH (24.1 ml; 393 mmol) and the reaction mixture was refluxed for 2hours. The solvent was evaporated off and the residue was trituratedwith ether, collected by filtration and dried under vacuum to give2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-N-hydroxyethanimidamide(14.5 g; 90% yield). ¹H NMR (400 MHz; DMSO-d₆): 3.98 (s, 3H), 4.58 (s,2H), 5.70 (s, 2H), 7.38 (s, 1H), 7.65 (d, 1H), 7.84 (s, 1H), 7.89 (dd,1H), 8.26 (d, 1H), 8.55 (s, 1H), 9.41 (s, 1H), 9.64 (s, 1H); MS (EI) forC₁₇H₁₅Cl₂N₅O₃: 408.05 (MH⁺).

To a solution of Boc-isonipecotic acid (4.72 g; 20.6 mmol) and4-methylmorpholine (5.7 ml; 51.5 mmol) in DMF (200 ml) were added HOBT(3.06 g; 22.7 mmol) and EDCI (4.35 g; 22.7 mmol) and the solution wasstirred at room temperature for 30 minutes. To the reaction mixture2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}-N-hydroxyethanimidamide(7 g; 17.1 mmol) was added and the solution was stirred at roomtemperature overnight. The solvent was removed under vacuum and theresidue was dissolved in ethyl acetate. The organic layer was washedwith saturated aqueous NaHCO₃, brine, dried over NaSO₄ and concentrated.

Procedure a) To the residue was added p-xylene (200 ml) and thesuspension was refluxed for two hours. The solvent was removed undervacuum and the residue was purified by column chromatography (SiO₂,hexanes/acetone from 4/1 to 1/1) to give 1,1-dimethylethyl4-[3-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate(8.3 g; 81% yield over two steps)

Procedure b) The residue was dissolved in THF (400 ml) and n-Bu₄NF (1Min THF; 17.1 ml; 17.1 mmol) was added. The reaction mixture was stirredat room temperature for 2 h. The solvent was evaporated off and theresidue was dissolved in ethyl acetate; the organic layer was washedwith H₂O, brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, hexanes/acetone) togive 1,1-dimethylethyl4-[3-({[4-[(3,4-dichlorophenyl)amino]6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate(6.9 g; 66% overall yield). ¹H NMR (400 MHz; DMSO-d₆): 1.40 (s, 9H),1.55-1.67 (m, 2H), 2.01-2.08 (m, 2H), 2.83-3.05 (br s, 2H), 3.33 (m,1H), 3.88-3.96 (m, 2H), 3.99 (s, 31H), 5.53 (s, 2H), 7.43 (s, 1H), 7.73(s, 2H), 8.02 (s, 1H), 8.1 (s, 1H), 8.81 (s, 1H), 10.74 (br s, 1H); MS(EI) for C₂₈H₃₀Cl₂N₆O₅: 601.09 (MH⁺)

1,1-Dimethylethyl4-[3-({[4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate(12.3 g, 20.4 mmol) was dissolved in MeOH (100 ml) and HCl (4M indioxane; 65 ml) was added. The solution was stirred at room temperaturefor 10 min and concentrated to half the initial volume. Ethyl ether wasadded to the suspension obtained and the precipitate was collected byfiltration, washed with ether and concentrated to dryness to give 8 g ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine(78% yield). ¹H NMR (400 MHz; DMSO-d₆): 1.61 (qd, 2H), 1.94 (m, 2H),2.07-2.19 (br s, 1H), 2.57 (td, 2H), 2.95 (dt, 2H), 3.17 (m, 1H), 3.97(s, 3H), 5.44 (s, 2H), 7.40 (s, 1H), 7.63 (d, 1H), 7.85 (s, 1H), 7.87(dd, 1H), 8.23 (d, 1H), 8.54 (s, 1H), 9.64 (s, 1H); MS (EI) forC₂₃H₂₂Cl₂N₆O₃: 501.07 (MH⁺)

Aqueous formaldehyde (37%, 894 ml, 12.0 mmol) was added to a solution ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine(1 g, 2.0 mmol) in formic acid (2 ml). The mixture was heated at 95° C.for two hours. The volatiles were removed under vacuum, the residue wasdissolved in CH₃OH and the pH of the solution was adjusted to 9 byaddition of Biorad AG® 1-X8 hydroxide form resin. The solution wasfiltered, concentrated in vacuo and the residue was crystallized fromMeOH/H₂O to giveN-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine(714 mg; 69% yield). ¹H NMR (400 MHz; DMSO-d₆): 1.69-1.82 (m, 2H),1.97-2.05 (m, 4H), 2.16 (s, 3H), 2.71-2.78 (m, 2H), 2.98-3.10 (m, 1H),3.96 (s, 3H), 5.44 (s, 2H), 7.39 (s, 1H), 7.62 (d, 1H), 7.83 (s, 1H),7.87 (dd, 1H), 8.22 (d, 1H), 8.53 (s, 1H), 9.63 (s, 1H); MS (EI) forC₂₄H₂₄Cl₂N₆O₃: 515.07 (MH⁺)

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(3,A-dichlorophenyl)-7-[({5-[(dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine

¹H NMR (400 MHz; DMSO-d₆): 2.26 (s, 6H), 3.87 (s, 2H), 3.97 (s, 3H),5.49 (s, 2H), 7.39 (s, 1H), 7.85-7.90 (m, 2H), 8.23 (d, 1H), 8.53 (s,1H), 9.67 (s, 1H); MS (EI) for C₂₁H₂₀Cl₂N₆O₃: 475.06 (MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-3-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine

¹H NMR (400 MHz; DMSO-d₆): 1.37-1.82 (m, 4H), 2.04-214 (m, 1H),2.20-2.34 (m, 1H), 2.70-2.87 (m, 2H), 3.07-3.22 (m, 2H), 3.97 (s, 3H),5.44 (s, 2H), 7.40 (s, 1H), 7.63 (d, 1H), 7.85 (s, 1H), 7.87 (dd, 1H),8.23 (d, 1H), 8.54 (s, 1H), 9.64 (s, 1H); MS (EI) for C₂₃H₂₂Cl₂N₆O₃:501.03 (MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine

¹H NMR (400 MHz; DMSO-d₆): 1.51-1.76 (m, 4H), 1.92-2.12 (m, 2H), 2.18(s, 3H), 2.30-2.40 (m, 1H), 251-258 (m, 1H), 2.87-2.94 (m, 1H) 3.97 (s,3H), 5.44 (s, 2H), 7.40 (s, 1H), 7.63 (d, 1H), 7.83-7.90 (m, 2H), 8.23(d, 1H), 8.54 (s, 1H), 9.64 (s, 1H); MS (EI) for C₂₄H₂₄Cl₂N₆O₃: 515.06(MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(piperidin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine

¹H NMR (400 MHz; DMSO-d₆): 1.26-1.50 (m, 4H), 1.52-1.72 (m, 2H),1.82-1.90 (m, 1H), 2.50-2.64 (m, 1H), 2.80-2.90 (m, 1H), 3.91 (s, 3H),5.41 (s, 2H), 7.35 (s, 1H), 7.58 (d, 1H), 7.80-7.86 (m, 2H), 8.19 (d,1H), 8.49 (s, 1H), 9.60 (s, 1H); MS (EI) for C₂₃H₂₂Cl₂N₆O₃: 501.11(MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz; DMSO-d₆): 1.61 (br m, 1H), 1.75-1.88 (br m, 3H), 2.08(br m, 1H), 2.28 (br d, 1H), 2.75 (s, 3H), 3.24 (br m, 1H), 3.49 (br m,2H), 4.05 (s, 3H), 5.08 (br s, 1H), 5.64 (s, 2H), 7.62 (s, 1H), 7.71 (d,1H), 7.87 (dd, 1H), 8.18 (d, 1H), 8.65 (s, 1H), 8.88 (s, 1H), 11.95 (s,1H); MS (EI) for C₂₄H₂₄Cl₂N₆O₃: 515.11 (MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-ethylpiperidin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-aminehydrochloride

¹H NMR (400 MHz; DMSO-d₆): 11.80 (br s, 1H), 8.87 (s, 1H), 8.56 (s, 1H),8.18 (d, 1H), 7.85 (dd, 1H), 7.73 (d, 1H), 7.60 (s, 1H), 5.65 (s, 2H),5.10 (br s, 1H), 4.05 (s, 3H), 3.80-3.50 (br m, 4H), 3.20-3.00 (br in,2H), 2.30-2.00 (br m, 1H), 1.95 (br m, 2H), 1.65 (br m, 1H), 1.20 (br m,3H); MS (EI) for C₂₅H₂₆Cl₂N₆O₃: 529 (MH⁺).

Example 31N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-2-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-aminehydrochloride (Method 2)

To a suspension of 50.0 g (0.41 mmol) benzoic acid in 150 mLN,N-dimethylformamide 70.0 g (0.50 mmol) potassium carbonate was addedand the mixture was stirred until the evolution of gas has ceased. Thereaction mixture was cooled to 0° C. and a solution of 29.0 mL (0.41mmol) bromoacetonitrile in 50 mL N,N-dimethylformamide was addeddropwise. The reaction mixture was stirred overnight at roomtemperature. The solvent was evaporated and the residue was dissolved in500 mL ethyl acetate. It was washed with water (3×150 mL), saturatedaqueous sodium hydrogencarbonate (150 mL) and brine. The organic layerwas separated and dried over anhydrous sodium sulfate. The drying agentwas filtered off and the solvent was evaporated. The resulting crudeproduct was purified by column chromatography (hexane-ethyl acetate 9:1to 4:1) to yield cyanomethyl benzoate 62.6 g (95%). ¹H-NMR (400 MHz;DMSO-d₆): 7.98 (m, 2H), 7.69 (m, 1H), 7.54 (m, 2H), 5.20 (s, 2H); GCMSfor C₉H₇NO₂: 161 (M⁺).

Cyanomethyl benzoate (22.2 g, 138 mmol) was dissolved in ethanol (250mL) followed by addition of 50% aqueous hydroxylamine (16.9 mL, 276mmol) and the mixture was stirred for 15 minutes at room temperature.Concentration followed by addition of water (250 mL) afforded acolorless crystalline solid that was collected by filtration and washedwith additional water then dried in vacuo to give2-(hydroxyamino)-2-iminoethyl benzoate (23.69 g, 88% yield). ¹H-NMR (400MHz; DMSO-d₆): 9.37 (s, 1H), 7.98 (m, 2H), 7.65 (m, 1H), 7.54 (tr, 2H),5.69 (br s, 2H), 4.64 (s, 2H).

Example 32N-(3,4-dichlorophenyl)-6-(methyloxy)-7[({3-[(4-methylpiperazin-1-yl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine

A mixture of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol(3.67 g), methyl bromoacetate (0.81 mL), and potassium carbonate (4.66g) in DMF (21 mL) was stirred at room temperature for 18 hours. Thereaction mixture was diluted with ethyl acetate and filtered. The solidwas combined with the filtrate and washed with water, dried over sodiumsulfate and evaporated to give a brown solid which was recrystallized inmethanol to give methyl{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetate(2.80 g) ¹H-NMR (400 MHz; DMSO-d₆): 9.62 (s, 1H), 8.46 (s, 1H), 8.24 (s,1H), 7.94-7.85 (m, 2H), 7.63 (d, 1H), 7.17 (s, 1H), 5.04 (s, 2H), 4.00(s, 3H), 3.72 (s, 3H); MS (EI) for C₁₈H₁₅N₃O₄Cl₂: 408 (MH⁺).

A mixture (4-methylpiperazin-1-yl)acetonitrile (400 mg), hydroxylamine(50% aqueous solution, 2.0 mL) and ethanol (10.0 mL), was stirred atroom temperature for 18 hours. The reaction mixture was evaporated todryness to give a crystalline solid that was washed with hexane anddried under vacuum to giveN-hydroxy-2-(4-methylpiperazin-1-yl)ethanimidamide (405 mg). ¹H-NMR (400MHz; CDCl₃): 5.19 (br s, 31H), 3.00 (s, 2H), 2.75-2.28 (br m, 8H), 2.70(s, 3H).

Sodium hydride (60% oil dispersion, 30 mg) was added to a mixture ofN-hydroxy-2-(4-methylpiperazin-1-yl)ethanimidamide (50 mg) and 3 Amolecular sieves (110 mg) in 1 mL of DMF. After the initial hydrogenevolution had stopped, the mixture was heated at 60° C. for 30 minutes.{[4-(3,4-Dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetate(50 mg) was added to the reaction mixture and the heating was continuedat 90° C. for one hour. The reaction was cooled to room temperature,diluted with methanol, and filtered. The filtrate was purified byreverse phase HPLC, and the eluent containing the expected product wasconcentrated to dryness and isolated as the TFA salt. The salt was takeninto methanol and treated with Biorad AG® i-X8 hydroxide form resin thenfiltered and the filtrate concentrated and dried in vacuo to give thetitle compound (25.0 mg) ¹H-NMR (400 MHz, DMSO-d₆): 10.60 (br s, 1H),8.78 (s, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H),7.22 (s, 1H), 5.78 (s, 2H), 4.00 (s, 3H), 3.82 (s, 2H), 3.15-2.90 (br m,4H), 2.80 (s, 3H), 2.60-2.45 (br m, 4H); MS (EI) for C₂₄H₂₅N₇O₃Cl₂: 530(MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(3,4-dichlorophenyl)-7-[({3-[(dimethylamino)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine

¹H NMR (400 MHz; DMSO-d₆): 10.48 (br s, 1H), 8.75 (s, 1H), 8.20 (s, 1H),8.05 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.25 (s, 1H), 5.85 (s, 2H),4.85 (s, 2H), 4.00 (s, 3H), 2.88 (s, 6H); MS (EI) for C₂₁H₂₀N₆O₃Cl₂: 475(MH⁺).

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(morpholin-4-ylmethyl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine

¹H-NMR (400 MHz, DMSO-d₆): 10.50 (br s, 1H), 8.78 (s, 1H), 8.18 (s, 1H),8.04 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.22 (s, 1H), 5.82 (s, 2H),4.37 (s, 2H), 4.00 (s, 3H), 3.78-3.70 (br m, 4H), 2.15-2.95 (br m, 4H);MS (EI) for C₂₄H₂₅N₇O₃Cl₂: 517 (MH⁺).

Example 33N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(4-methylpiperazin-1-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine

1,1-Dimethylethyl 1-piperazinecarboxylate (25 g, 134.2 mmol) was takeninto THF (100 mL) followed by addition of triethylamine (25 mL, 178mmol). The solution was cooled to 0° C. followed by addition dropwiseaddition of cyanogen bromide (15.6 g, 147.6 mmol) in THF (100 mL) andthe resulting mixture was allowed to warm to room temperature thenstirred an additional 12 hours. The reaction mixture was concentrated invacuo and partitioned with ethyl ether and water. The organic layer waswashed once with saturated aqueous NaCl then dried over anhydrousmagnesium sulfate followed by concentration to afford 1,1-dimethylethyl4-cyanopiperazine-1-carboxylate (24.5 g, 86% yield) as a colorlesscrystalline solid. ¹H-NMR (400 MHz, CDCl₃): 3.51 (tr, 4H) 3.19 (t, 4H),1.46 (s, 9H).

1,1-Dimethylethyl 4-cyanopiperazine-1-carboxylate (10 g, 47.1 mmol) wastaken into ethanol (100 mL) and the resulting solution was cooled to 0°C. I-Hydroxylamine (50% aqueous solution, 3.5 mL, 56.5 mmol) was addedand the mixture was allowed to warm to room temperature then stirred anadditional hour. The mixture was then concentrated in vacuo to a pasteand suspended in 1:1 ethyl ether/hexane (100 mL) and the solid productcollected by filtration. The solid was washed with an additional portionof ethyl ether/hexane then dried to give 1,1-dimethylethyl4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (9.64 g, 83%yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆): 8.34 (s, 1H), 5.19(s, 2H), 3.30 (tr, 4H), 2.91 (tr, 4H), 1.39 (s, 9H).

1,1-Dimethylethyl4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (3.58 g, 14.6mmol) was suspended in THF (50 mL) followed by the addition ofdiisopropylethylamine (3.0 mL, 17.5 mmol) and the mixture was cooled to0° C. Acetoxyacetyl chloride (1.6 mL, 14.6 mmol) was added by syringeand the mixture was allowed to stir an additional 30 minutes at 0° C.The resulting homogeneous solution was allowed to warm to roomtemperature then concentrated in vacuo to afford a white solid residue.The material was suspended in water (50 ml) and the solid product wascollected by filtration, washed with additional water then hexanes anddried in vacuo. The intermediate O-acyl derivative was then suspended inTHF (50 mL) followed by addition of TBAF (1.0M in THF, 3.5 mL) and themixture was stirred for 30 minutes at room temperature. The homogeneoussolution obtained was concentrated in vacuo and the residue partitionedwith ethyl ether and water. The organic layer was washed twice withadditional water then with saturated aqueous sodium chloride and driedover anhydrous magnesium sulfate. Filtration and concentration gave1,1-dimethylethyl4-{5-[(acetoxy)methyl]-1,2,4-oxadiazol-3-yl}piperazine-1-carboxylate(3.6 g, 76% yield) as a colorless crystalline solid. ¹H-NMR (400 MHz,CDCl₃): 5.14 (s, 2H), 3.51 (tr, 4H), 3.42 (tr, 4H), 2.18 (s, 3H), 1.48(s, 9H).

1,1-Dimethylethyl4-{5-[(acetoxy)methyl]-1,2,4-oxadiazol-3-yl}piperazine-1-carboxylate(13.57 g, 41.6 mmol) was dissolved in methanol (100 mL) followed byaddition of aqueous sodium hydroxide (4M, 10.4 mL) and the mixture wasstirred for 30 minutes at room temperature. The reaction mixture wasthen concentrated in vacuo and the residue partitioned with ethylacetate and 0.1 M aqueous hydrochloric acid. The organic layer was thenwashed with saturated aqueous sodium chloride then dried over anhydrousmagnesium sulfate. Filtration and concentration afforded1,1-dimethylethyl4-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate(10.51 g, 89% yield) as a colorless crystalline solid. ¹H-NMR (400 MHz,CDCl₃): 4.75 (s, 2H), 3.53-3.50 (m, 4H), 3.44-3.42 (m, 4H), 3.20 (br s,1H), 1.48 (s, 9H).

1,1-Dimethylethyl4-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (7.4g, 26 mmol) was taken into dichloromethane (100 mL) followed by additionof pyridine (5.3 mL, 65 mmol) and the solution was cooled to 0° C.Thionyl chloride (2.3 mL, 31.2 mmol) was added by syringe and themixture was allowed to warm to room temperature and stirred anadditional 12 hours. The mixture was then concentrated in vacuo and theresidue partitioned with ethyl acetate and water. The aqueous phase wasextracted twice with ethyl acetate and the combined organic layers werewashed once with 0.1M aqueous hydrochloric acid then saturatedaqueoussodium chloride and dried over anhydrous magnesium sulfate. Filtration,concentration and purification of the residue by silica gel flashchromatography using 3:1 hexanes:ethyl acetate provided1,1-dimethylethyl4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (4.82g, 61% yield) as a slightly yellow crystalline solid. ¹H-NMR (400 MHz,CDCl₃): 4.53 (s, 2H), 3.51 (tr, 4H), 3.43 (tr, 4H), 1.48 (s, 9H).

1,1-dimethylethyl4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (173.6mg, 0.57 mmol),4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (154 mg, 0.46mmol) and potassium carbonate (315 mg, 2.85 mmol) were taken into DMF (2mL) and the mixture was heated to 50° C. for one hour. The mixture wasthen cooled to room temperature and partitioned with ethyl acetate andwater. The organic layer was washed once more with water and the organiclayer was partitioned again with water. A precipitate forms in theorganic layer at this point and hexanes was added to the biphasicmixture in portions until formation of the precipitate is complete. Thesolid product was then collected by filtration. The solid residue wassuspended in hot methanol and diluted with water followed by collectionof the solid by filtration. The solid was washed with ethyl ether anddried in vacuo to give 1,1-dimethylethyl4-[5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate(170.7 mg, 62% yield) as a tan solid. ¹H-NMR (400 MHz, DMSO-d₆): 9.65(s, 1H), 8.54 (s, 1H), 8.23 (d, 1H), 7.88-7.86 (m, 2H), 7.63 (d, 1H),7.32 (s, 1H), 5.58 (s, 2H), 3.98 (s, 3H), 3.43-3.40 (m, 41), 3.34-3.32(m, 4H), 1.41 (s, 9H); MS (ET) for C₂₇H₂₉Cl₂N₇O₅: 602 (MH⁺).

1,1-dimethylethyl4-[5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-oxadiazol-3-yl]piperazine-1-carboxylate(170 mg, 0.28 mmol) was taken into methanol (2.5 mL) followed byaddition of anhydrous hydrogen chloride in dioxane (4M, 2.5 mL) and themixture was brought to reflux then immediately allowed to cool to roomtemperature over 5 minutes. The mixture was then concentrated in vacuoto a slurry followed by addition of excess ethyl ether. The solidresidue was collected by filtration and dried in vacuo to giveN-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-piperazin-1-yl-1,2,4-oxadiazol-5-yl)methyl}oxyquinazolin-4-aminehydrochloride (145 mg, 100% yield) as a tan solid. ¹H-NMR (400 MHz,DMSO-d₆): (hydrochloride) 11.98 (s, 1H), 9.54 (br s, 2H), 8.87 (s, 1H),8.66 (s, 1H), 8.17 (d, 1H), 7.86 (dd, 1H), 7.70 (d, 1H), 7.47 (s, 1H),5.66 (s, 2H), 4.06 (s, 3H), 3.64-3.61 (m, 4H), 3.19-3.16 (m, 4H); (freebase) 9.69 (s, 1H), 8.53 (s, 1H), 8.24 (d, 1H), 7.90-7.87 (m, 2H), 7.62(d, 1H), 7.31 (s, 1H), 5.56 (s, 2H), 3.99 (s, 3H), 3.31-3.29 (m, 4H),2.81-2.79 (m, 4H); MS (EI) for C₂₂H₂₁Cl₂N₇O₃: 502 (MH⁺).

N-(3,4-dichlorophenyl)-6-(methloxy)-7-{[(3-piperazin-1-yl-1,2,4-oxadiazol-5-yl)methyl}oxyquinazolin-4-aminehydrochloride (66 mg, 0.12 mmol) was suspended in methanol (5 mL)followed by addition of Bio-Rad AG®1-X8 hydroxide form resin until pH 8.The resin was then removed by filtration and the methanol solution wasconcentrated in vacuo. The residue was taken into formic acid (2 mL) and37 W % aqueous formaldehyde (50 uL, 0.6 mmol) was added. The mixture washeated to 90° C. for 2.5 hours then concentrated in vacuo. The residuewas taken into 1 mL of methanol and the solution acidified by additionof 4M anhydrous hydrogen chloride in dioxane to pH 2. Portionwiseaddition of ethyl ether afforded a crystalline solid that was collectedby filtration and dried to giveN-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(4-methylpiperazin-1-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-aminehydrochloride (53.9 mg, 80% yield) as a tan solid. ¹H-NMR (400 MHzDMSO-d₆): 11.98 (s, 1H), 11.39 (s, 1H), 8.87 (s, 1H), 8.65 (s, 1H), 8.17(d, 1H), 7.86 (dd, 1H), 7.69 (d, 1H), 7.48 (s, 1H), 5.67 (s, 2H), 4.06(s, 3H), 3.95 (br d, 2H), 3.49-3.46 (m, 4H), 3.15 (br m, 2H), 2.78 (s,3H) MS (EI) for C₂₃H₂₃Cl₂N₇O₃: 516 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(4-ethylpiperazin-1-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-aminehydrochloride

¹H-NMR (400 MHz, DMSO-d₆):

Example 34N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}quinazolin-4-aminehydrochloride

To a solution of{[4-[3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetonitrile(0.450 g, 1.20 mmol) in DMF (2 mL) was added NEt₃ (0.30 mL, 2.2 mmol).Hydrogen sulfide (g) was bubbled through the solution until saturation(5 min.). The solution was then heated to 70° C. and it turned darkgreen. After 0.5 h, the solution was cooled to room temperature, 0.20 mLNEt₃ (1.4 mmol) was added, and H₂S (g) was bubbled through for 5 min.The solution was again heated to 70° C. for 1.5 h. The solvent wasremoved in vacuo and the product was crystallized from MeOH to yield0.459 g (94%) of2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethanethioamideas a yellow solid. ¹H NMR (400 MHz, d₆-DMSO): 10.07 (s, 1H), 9.68 (s,1H), 9.29 (s, 1H), 8.55 (s, 1H), 8.26 (d, 1H), 7.91 (m, 2H), 7.66 (d,1H), 7.10 (s, 1H), 4.96 (s, 1H), 4.01 (s, 3H), 2.73 (d, 2H); MS (EI) forC₁₇H₁₄N₄O₂SCl₂: 409 (M⁺).

To a solution of2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethanethioamide(0.300 g, 0.733 mmol) in DMF (5 mL) was added 1,1-dimethylethyl3-bromo-4-oxopiperidine-1-carboxylate (0.310 g, 1.11 mmol). The solutionwas stirred at 60° C. for 72 h. An additional 0.100 g (0.360 mmol) of1,1-dimethylethyl 3-bromo-4-oxopiperidine-1-carboxylate was added to thereaction mixture, which was then heated at 60° C. for an additional 24h. The solvent was removed in vacuo and the crude reaction mixture waspurified via column chromatography (SiO₂, 50% hexanes/ethyl acetate).This intermediate was then subjected to 10% TFA in CH₂C₂ at roomtemperature. After removal of the solvent, the crude amine salt wastaken up in fresh MeOH and treated with Bio-Rad AG 1-X8 resin hydroxideform until pH 8. Filtration and concentration in vacuo provided 0.247 g(69%) ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amineas a brown oil.

¹H NMR (400 MHz, d₆-DMSO): 9.68 (s, 1H), 8.43 (s, 1H), 8.24 (d, 1H),7.89 (d, 1H), 7.87 (d, 1H), 7.62 (d, 1H), 7.37 (s, 1H), 5.54 (s, 2H),3.98 (s, 3H), 3.87 (s, 2H), 2.97 (t, 2H), 2.66 (t, 2H); MS (EI) forC₂₂H₁₉N₅O₅SCl₂: 488 (M⁺)

N-(3,4-Dichlorophenyl)-6-(menthyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine(0.247 g, 0.506 mmol) was combined with 37% aqueous formaldehyde (0.23mL, 3.1 mmol) in formic acid (2 mL) and the solution was heated at 95°C. for 1 h. The solvent was removed in vacuo and the residue waspurified via HPLC (reverse-phase, CH₃CN/H₂O with 0.1% TFA). Upon removalof CH₃CN/H₂O, the product was taken up in MeOH and treated with Bio-RadAG 1-X8 resin hydroxide form until pH 8. The product was filtered andconcentrated in vacuo, then taken up in fresh MeOH and treated with 4.0M HCl/dioxane (0.050 mL). Removal of solvent in vacuo provided 0.085 g(31%) ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}quinazolin-4-aminehydrochloride as a pale yellow solid. ¹H NMR (400 MHz, d₆-DMSO): 8.69(s, 1H), 8.24 (d, 1H), 8.11 (s, 1H), 7.89 (dd, 1H), 7.70 (d, 1H), 7.42(s, 1H), 5.65 (s, 3H), 4.65 (m, 1H), 4.40 (m, 1H), 4.02 (s, 3H), 3.70(m, 1H), 3.12 (m, 2H), 2.94 (s, 4H); MS (EI) for C₂₃H₂₁N₅O₂SCl₂: 502(M⁺).

Example 35N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride

N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine(0.249 g, 0.510 mmol) was taken up in 50% THF/MeOH (10 mL) and thesolution was cooled with an ice bath. Acetaldehyde (0.057 mL, 1.0 mmol),followed by NaCNBH₃ (0.038 g, 0.61 mmol) were added. The solution wasallowed to warm to room temperature. After 4 h, additional acetaldehyde(0.050 mL, 0.89 mmol) and NaCNBH₃ (0.040 g, 0.64 mmol) were added andthe solution was stirred for 12 h. An additional 0.050 mL (0.89 mmol) ofacetaldehyde and NaCNBH₃ (0.020 g, 0.32 mmol) were added. The solutionwas poured into 10% MeOH/ethyl acetate (100 mL) and washed once with H₂O(100 mL). The organic layer was dried (Na₂SO₄); filtered and the solventwas removed in vacuo. The crude product was purified via preparativeHPLC (reverse phase, CH₃CN/H₂O/NH₄OAc/AcOH). The solvents were removed,the product was taken up in MeOH and treated with 4.0M HCl/dioxane(0.025 mL), and lyophilized to provide 0036 g (12%) ofN-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-aminehydrochloride as a yellow solid.

¹H NMR (400 MHz, d₆-DMSO): 9.56 (broad s, 1H), 8.85 (s, 1H), 8.37 (broads, 1H), 8.15 (d, 1H), 7.81 (dd, 1H), 7.73 (d, 1H), 7.48 (s, 1H), 5.66(s, 2H), 4.71 (d, 1H), 4.36 (m, 1H), 4.04 (s, 3H), 3.74 (m, 1H), 3.13(m, 3H), 1.32 (t, 3H); MS (EI) for C₂₄H₂₃N₅O₅SCl₂: 516 (M⁺).

Example 36N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-aminehydrochloride

1,1-Dimethylethyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.50g, 6.14 mmol), NaHCO₃ (0.570 g, 6.78 mmol) and 1,3-dichloroacetone(0.860 g, 6.77 mmol) were combined in 1,2-dichloroethane (4 mL) and thereaction mixture was stirred at room temperature for 12 h. The crudereaction mixture was filtered using CH₂Cl₂ and the filtrate wasconcentrated in vacuo until approximately 30 mL of solvent remained. Tothis solution was added pyridine (0.75 mL, 9.2 mmol), and the solutionwas cooled with an ice bath. Thionyl chloride (0.49 mL, 6.8 mmol) wasadded and the solution was allowed to warm slowly to room temperature.The solvent was removed in vacuo and the residue was taken up in 10%MeOH/ethyl acetate (100 mL). The organic layer was washed with H₂O (100mL) and brine (100 mL), dried (Na₂SO₄), filtered, and concentrated invacuo to yield 2.24 g (>100%) of crude 1,1-dimethylethyl4-[4-(chloromethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as acolorless oil. ¹H NMR (400 MHz, d₆-DMSO): 7.62 (s, 1H), 4.60 (s, 2H),3.98 (m, 1H), 3.63 (dd, 2H), 3.16 (m, 1H), 2.90 (broad s, 2H), 201 (dd,1H), 1.51 (m, 2H),1.40 (s, 9H) MS (EI) for C₁₄H₂₁N₂O₂SCl: 261 (M-tBu).

To a solution of4-[3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (1.00 g, 2.97mmol) in DMF (10 mL) was added 1,1-dimethylethyl4-[4-(chloromethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.04 g,3.28 mmol) and K₂CO₃ (2.06 g, 14.9 mmol). The solution was heated to 70°C. for 12 h, and then the solvent was removed in vacuo. The residue wastaken up in 10% MeOH/ethyl acetate (100 mL) and washed with H₂O (100mL). The organic layer was dried (Na₂SO₄), filtered and concentrated invacuo. Column chromatography (SiO₂, 50% hexanes/acetone) yielded 0.642 g(35%) of crude 1,1-dimethylethyl4-[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate.Half of this intermediate (0.300 g) was then subjected to 10% TFA inCH₂Cl₂ at room temperature for 1 hi then concentrated in vacuo. Theresidue was dissolved in MeOH (50 mL) and treated with Bio-Rad AG 1-X8resin hydroxide form to pH 8. Filtration and concentration in vacuoprovided 0.230 g (92% from 1,1-dimethylethyl4-[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate)ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amineas a brown oil. MS (EI) for C₂₄H₂₃N₅O₂SCl₂: 516 (M⁺).

N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine(0078 g, 0.15 mmol) was combined with 37% aqueous formaldehyde (0.025mL, 0.34 mmol) in formic acid (2 mL) and the solution was heated to 95°C. for 1 h. The solvent was removed in vacuo and the residue was takenup in 10% MeOH/ethyl acetate (100 mL) and washed with saturated NaHCO₃(aq) (100 mL). The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. Trituration from MeOH and treatment of theresultant yellow solid with 4.0 M HCl/dioxane (0.050 mL) in MeOH,followed by lyophilization, provided 0.032 g (37%) ofN-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-aminehydrochloride as a pale yellow solid. ¹H NMR (400 MHz, d₆-DMSO): 8.55(s, 1H), 8.25 (d, 1H), 7.89 (dd, 2H), 7.76 (s, 1H), 7.63 (d, 1H), 7.41(s, 1H), 5.30 (s, 2H), 3.96 (s, 3H), 3.52 (d, 2H), 3.29 (m, 2H), 3.08(m, 1H), 2.79 (s, 3H), 2.29 (d, 2H), 1.95 (m, 2H); MS (EI) forC₂₆H₂₅N₅O₂SCl₂: 530 (M⁺).

Example 37N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-aminehydrochloride

N-(3,4-Dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3-thiazol-4-yl)methyl]oxy}quinazolin-4-amine(0.230 g, 0.445 mmol) was taken up in 50% MeOH/THF (10 mL) and cooledwith an ice bath. Acetaldehyde (0.050 mL, 0.89 mmol) was added, followedby NaCNBH₃ (0.034 g, 0.54 mmol) and the solution was allowed to warm toroom temperature. After 1.5 h, 0.016 g (0.25 mmol) of additional NaCNBH₃was added and the solution was stirred for 12 h. The reaction mixturewas poured into ethyl acetate (100 mL), washed with saturated NaHCO₃(aq) (50 mL) and dried (Na₂SO₄). Filtration and concentration in vacuowas followed by preparative HPLC (reverse-phase, CH₃CN/H₂O with 0.01%TFA). This product was neutralized (NaHCO₃) to give 0.167 g (0.306 mmol)of free amine, which was taken up in MeOH (50 mL) and treated with 4.0 MHCl/dioxane (0.077 mL, 0.31 mmol). Lyophilization provided 0.105 g (41%)ofN-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride as a pale yellow solid. ¹H NMR(400 MHz, do-DMSO): 8.65 (broad s, 1H), 8.23 (d, 1H), 8.08 (broad s,1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.66 (d, 1H), 7.47 (s, 1H), 5.32 (s,2H), 3.98 (s, 3H), 3.55 (d, 2H), 3.01-3.11 (m, 5H), 2.29 (m, 2H), 2.04(m, 2-1H), 1.26 (t, 3H); MS (EI) for C₂₆H₂₇N₅O₂SCl₂: 544 (M⁺).

Assays

Generally for assay of activity, either ephrin, EGFR, or a compoundaccording to the invention is non-diffusably bound to an insolublesupport having isolated sample-receiving areas (for example, amicrotiter plate, an array, etc.). The insoluble support may be made ofany composition to which the compositions can be bound, is readilyseparated from soluble material, and is otherwise compatible with theoverall method of screening. The surface of such supports may be solidor porous and of any convenient shape. Examples of suitable insolublesupports include microtiter plates, arrays, membranes and beads. Theseare typically made of glass, plastic (for example, polystyrene),polysaccharides, nylon or nitrocellulose, Teflon™, etc. Microtiterplates and arrays are especially convenient because a large number ofassays can be carried out simultaneously, using small amounts ofreagents and samples. The particular manner of binding of thecomposition is not crucial so long as it is compatible with the reagentsand overall methods of the invention, maintains the activity of thecomposition and is nondiffusable. Exemplary methods of binding includethe use of antibodies (which do not sterically block either the ligandbinding site or activation sequence when the protein is bound to thesupport), direct binding to “sticky” or ionic supports, chemicalcrosslinking, the synthesis of the protein or agent on the surface, etc.Following binding of the protein or agent, excess unbound material isremoved by washing. The sample receiving areas may then be blockedthrough incubation with bovine serum albumin (BSA), casein or otherinnocuous protein or other moiety.

One measure of inhibition is K_(i). For compounds with IC₅₀'s less than1 μM, the K_(i) or K_(d) is defined as the dissociation rate constantfor the interaction of the agent with ephrin or EGFR. Exemplarycompositions have K_(i)'s of, for example, less than about 100 μM, lessthan about 10 μM, less than about 1 μM, and further for example havingK_(i)'s of less than about 100 nM, and still further, for example, lessthan about 10 nM. The K_(i) for a compound is determined from the IC₅₀based on three assumptions. First, only one compound molecule binds tothe enzyme and there is no cooperativity. Second, the concentrations ofactive enzyme and the compound tested are known (i.e., there are nosignificant amounts of impurities or inactive forms in thepreparations). Third, the enzymatic rate of the enzyme-inhibitor complexis zero. The rate (i.e., compound concentration) data are fitted to theequation:

$V = {V_{\max}{E_{0}\left\lbrack {I - \frac{\left( {E_{0} + I_{0} + K_{d}} \right) - {\sqrt{\left( {E_{0} + I_{0} + K_{d}} \right)^{2} - {4E_{0}}}I_{0}}}{2E_{0}}} \right\rbrack}}$

-   -   Where V is the observed rate, V_(max), is the rate of the free        enzyme, I₀ is the inhibitor concentration, E₀ is the enzyme        concentration, and K_(d) is the dissociation constant of the        enzyme-inhibitor complex.

Another measure of inhibition is GI₅₀, defined as the concentration ofthe compound that results in a decrease in the rate of cell growth byfifty percent. Exemplary compounds have GI₅₀'s of, for example, lessthan about 1 mM, less than about 10 μM, less than about 1 μM, andfurther, for example, having GI₅₀'s of less than about 100 nM, stillfurther having (Iso's of less than about 10 nM. Measurement of GI₅₀ isdone using a cell proliferation assay.

Tyrosine kinase activity is determined by 1) measurement ofkinase-dependent ATP consumption by in the presence of a genericsubstrate such as polyglutainine, tyrosine (pEY), byluciferase/luciferin-mediated chemiluminescence or; 2) incorporation ofradioactive phosphate derived from ³³P-ATP into a generic substratewhich has been adsorbed onto the well surface of polystyrene microtiterplates. Phosphorylated substrate products are quantified byscintillation spectrometry.

Materials and Methods

Kinase activity and compound inhibition are investigated using one ormore of the three assay formats described below. A brief summary ofassay conditions is listed in Table 2. The ATP concentrations areselected near its Michaelis-Menten constant (K_(M)) for each individualkinase. Dose-response experiments are performed at ten differentinhibitor concentrations in a 384-well plate format. The data are fittedto a standard four-parameter equation listed below:

Y=Min−(Max−Min)/(1+(X/IC ₅₀)̂H)

-   -   where Y is the observed signal, X is the inhibitor        concentration, Min is the background signal in the absence of        enzyme (0% enzyme activity), Max is the signal in the absence of        inhibitor (100% enzyme activity), IC₅₀ is the inhibitor        concentration at 50% enzyme inhibition and H represents the        empirical Hill's slope to measure the cooperativity. Typically H        is close to unity. These parameters are obtained by nonlinear        regression algorithm built into ActivityBase software (available        from ID Business Solutions Ltd., of Guildford, Surrey, UK).

³³P phosphoryl transfer assay (radiometric)

Greiner 384-well white clear bottom high binding plates (available fromGreiner Bio-One, Inc., of Longwood, Fla.) are coated with 2 μg/well ofprotein or peptide substrate in a 50 μL volume overnight at ambienttemperature. The coating buffer contains 40 μg/mL substrate, 22.5 mMNa₂CO₃, 27.5 mM NaHCO₃, 150 mM NaCl and 3 mM NaN₃. The coating solutionis aspirated and the plates are washed once with 50 μL of assay bufferand padded dry. Subsequently compounds and enzymes are mixed with γ³³P-ATP (3.3 μCi/mmol) in a total volume of 20 uL in suitable assaybuffers (see Table 2). For example the final EphB4 reaction solutioncontains 20 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 0.01% Triton X-100, 0.1 mMNaVO₃, 5 nM EphB4 enzyme and 5 μM ATP. The mixture is incubated atambient temperature for 1.5-2.5 hrs as indicated in Table 2 and stoppedby aspirating using an EMBLA 96-head washer. The plates are subsequentlywashed 6-12 times with PBST or TBS buffer. Scintillation fluid (50μl/well) is then added, the plates are sealed and activity assessed byliquid scintillation spectrometry on a Perkin Elmer MicroBeta TriLux(available from PerkinElmer Life and Analytical Sciences, Inc., ofBoston Mass.).

Luciferase-Coupled Chemiluminescent Assay (LCCA)

In the LCCA assays, kinase activity is measured by the ATP consumptionthat is accurately measured by luciferase-coupled chemiluminescence.Greiner 384-well white clear bottom medium binding plates are used forLCCA. Briefly the kinase reaction is initiated by mixing compounds, ATPand kinases in a 20 μL volume. The mixture is incubated at ambienttemperature for 2-4 hrs as indicated in Table 2. At the end of thekinase reaction, a 20 μL luciferase-luciferin mix is added and thechemiluminescent signal is read on a Wallac Victor² reader. Theluciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5 ug/mLoxalic acid (pH 78), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mLcoenzyme A, 63 M AMP, 28 ug/mL luciferin and 40,000 units of light/mLluciferase. For the LCCA assays, the ATP consumption has been kept at25-45%, where the decrease in substrate concentration has less than 35%effect on IC₅₀ values compared to the “theoretical” values with nosubstrate turnover. The IC₅₀ values correlates well with those ofradiometric assays.

AlphaScreen

In AlphaScreen, when the donor and acceptor beads are close inproximity, a series of photochemical events will give rise to afluorescent signal upon light activation. Here we use biotinylatedpoly-(Glu, Tyr) 4:1 as the kinase substrate, streptavidin-coated donorbeads and anti-phosphotyrosine antibody PY100-coated acceptor beads.Upon phosphorylation, the peptide substrate can bind to both donor andacceptor beads, thus gives rise to fluorescence. Compounds, ATP,biotinylated poly-(Glu, Tyr) and kinases are mixed in a volume of 20 μLfor 1 hr at ambient temperature using Greiner 384-well white clearbottom medium binding plates. Then 10 uL solution containing 15-30 mg/mLAlphaScreen beads, 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3%BSA and 0.03% Tween-20 is added to each well. After 2-16 hr incubationof the beads, plates are read in a Perkin Elmer AlphaQuest reader(available from PerkinElmer Life and Analytical Sciences, Inc., ofBoston Mass.). The IC₅₀ values correlate well with those of radiometricassays.

Enzymes were purchased from Proqinase (of Freiburg, Germany) and Panvera(of Madison, Wis.).

TABLE 2 Incubation Enzyme Enzyme Enzyme Assay format [E] [ATP] Substrate[Substrate] Time (min) Assay Buffer Construct/Preparation Source EphB4Radiometric 5 nM 5 μM poly-AEKY 2 μg/well 150 20 mM TrisHCl, Kinasedomain E605-E890 PanVera pH 7.5, 10 mM with N-terminal His6 tag isMgCl₂, 0.1 mM expressed in baculovirus NaVO₃, 0.01% and purified by IMACTriton chromatography. EphA2 LCCA 20 nM  3 μM poly-EY 1.6 μM 180 20 mMTrisHCl, N598-R890 with N-terminal PanVera pH 7.5, 10 mM His6 tag isexpressed in MgCl₂, 3 mM baculovirus and purified by MnCl₂, 0.01% IMACchromatography. Triton EGFR LCCA 7 nM 3 μM poly-EY 1.6 μM 210 20 mMTrisHCl, amino acids H672-A1210, ProQinase 11 nM  pH 7.5, 10 mMN-terminally fused to GST- MgCl₂, 3 mM HIS6-Thrombin cleavage MnCl₂, 1mM site, expressed in DTT, 0.01% baculovirus, one-step Triton affinitiypurification using GSH-agarose ErbB2 Alphascreen 1 nM 3 μM poly-EY 5 nM60 20 mM TrisHCl, Kinase domain Q679-V1255 ProQinase pH 7.5, 10 mM withN-terminal MgCl₂, 3 mM GST-HIS6 tag is expressed MnCl₂, 1 mM inbaculovirus infected Sf9 DTT, 0.01% cells and purified by GSH- Tritonagarose KDR LCCA 5 nM 3 μM poly-EY 1.6 μM 240 20 mM TrisHCl, Human KDRc-DNA, Amino ProQinase 6 nM pH 7.5, 10 mM Acids D807-V1356, N- MgCl₂, 3mM terminally fused to GST. MnCl₂, 1 mM One-step affinity purificationDTT, 0.01% using GSH-agarose Triton Flt-1 Radiometric 6 nM 5 μM poly-EY2 μg/well 120 20 mM TrisHCl, Human VEGF-R1 c-DNA, ProQinase pH 7.5, 10mM cytoplasmic domain, N- MgCl₂, 3 mM terminally fused to GST- MnCl₂, 1mM Factor X cleavage site. DTT, 0.01% One-step affinity purificationTriton using GSH-agarose

Structure Activity Relationships

Tables 3-6 show structure activity relationship data for selectedcompounds of the invention. As the data indicates, compounds of theinvention fall into different classes; some are “spectrum selective”(supra), some are selective for Ephrin, some selective for EGFR, andsome inhibit Ephrin and EGFR selectively, for example. Inhibition isindicated as IC₅₀ with the following key: A=IC₅₀ less than 50 nM, B=IC₅₀greater than 50 nM, but less than 1000 nM, C=IC₅₀ greater than 1000 nM,but less than 20,000 nM, and D=IC₅₀ greater than 20,000 nM.Abbreviations for enzymes listed in Tables 3-6 are defined as follows:EphB4 and EphA2 refer to ephrin receptor tyrosine kinse family membersephrin B4 and A2; KDR, kinase insert domain receptor tyrosine kinase,and Fit-1, fins-like tyrosine kinase-1, are representative of the FLKfamily or receptor tyrosine kinases; EGFR, epidermal growth factorreceptor tyrosine kinase, and ErbB2 are representative of the HER familyof receptor tyrosine kinases.

TABLE 3 EphB4 EphA2 KDR Flt-1 EGFR ErbB2 Entry Name IC₅₀ IC₅₀ IC₅₀ IC₅₀IC₅₀ IC₅₀ 1 N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2- A A A BA A methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 8N-(4-bromo-2,3-dichlorophenyl)-7-{[(3R,9aS)-hexahydro- B B B C A C1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 9N-(4,5-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- B B B B A B[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 10N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3R,9aS)- B B B B A Bhexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 11N-(3-chloro-2,4-difluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- B B B B A B[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 12N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- A A A A A A[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 13N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,9aS)- A A A A A Ahexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 14N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- A B B B A B[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 15N-(3,4-dichlorophenyl)-7-[(hexahydro-1H-[1,4]oxazino[3,4- A B A B A Ac][1,4]oxazin-3-ylmethyl)oxy]-6-(methyloxy)quinazolin-4- amine 16N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,9aS)-hexahydro-1H- A B B B A B[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 17N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,9aS)-hexahydro- A B B B A C1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 18N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,9aS)- A B B B A Bhexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 19N-(3,4-dichloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H- A B A B A B[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 20N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)- B B A B A Bhexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 21N-(3,4-dichlorophenyl)-7-{[(3R,8aR)-hexahydro-1H- A B A B A Bpyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 22N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(3S,8aS)- A A A B A Bhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 23N-(3,4-dichlorophenyl)-7-{[(3S,8aR)-hexahydro-1H- A A A B A Apyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 24N-(3,4-dichlorophenyl)-7-{[(3S,8aS)-hexahydro-1H- A A A B A Bpyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 25N-(3,4-dichlorophenyl)-7-{[(3R,8aS)-hexahydro-1H- A A A B A Apyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 26N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- A A A B A Bpyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 27N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3S,8aS)- A A A A A Bhexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 28N-(3-chloro-2,4-difluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- A A B B A Bpyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 29N-(4-bromo-2,3-dichlorophenyl)-7-{[(3S,8aS)-hexahydro- A A A B A B1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 30N-(4,5-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H- A A A B A Bpyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine 32 1,4:3,6-dianhydro-5-deoxy-5-({[4-[(3,4-B C B C A B dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-glucitol 361,4:3,6-dianhydro-5-({[4-[(4-bromo-2,3- A C B C A Cdichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-5-deoxy-2-O-methyl-D-glucitol 381,4:3,6-dianhydro-5-deoxy-5-({[4-[(4,5-dichloro-2- B B B C A Bfluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-O-methyl-D-glucitol 39(3S,9aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- A A A B A C(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one 40(3S,9aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- A B B B A C(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one 41(3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- A B A B A B(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 42(3S,8aR)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- A A A B A C(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 43(3S,8aS)-3-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- A B A B A C(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 44(3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- A B B B A C(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one 46N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(8aR)-tetrahydro- A B B B A B1H-[1,3]thiazolo[4,3-c][1,4]oxazin-6-ylmethyl]oxy}quinazolin- 4-amine 49N-(3,4-dichlorophenyl)-7-{[(3aR,6aS)-2- B B B C A Bmethyloctahydrocyclopenta[c]pyrrol-5-yl]oxy}-6-(methyloxy)quinazolin-4-amine 511,4:3,6-dianhydro-2-O-[4-[(4-bromo-5-chloro-2- B C C C A Cfluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O- methyl-L-iditol52 1,4:3,6-dianhydro-2-O-[4-[(3,4-dichloro-2- A C C C A Bfluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O- methyl-L-iditol53 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chloro-2- B C B C A Bfluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O- methyl-L-iditol54 1,4:3,6-dianhydro-2-O-methyl-5-O-{6-(methyloxy)-4-[(2,3,4- B C C C AC trichlorophenyl)amino]quinazolin-7-yl}-L-iditol 551,4:3,6-dianhydro-5-O-[4-[(3,4-dichlorophenyl)amino]-6- B B C A B(methyloxy)quinazolin-7-yl]-2-O-methyl-D-xylo-hexitol 561,4:3,6-dianhydro-2-O-[4-[(4-bromo-2,3- B C C C A Bdichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O- methyl-L-iditol57 dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C C A B(methyloxy)quinazolin-7-yl]-L-sorbose ethylene glycol acetal 581,4:3,6-dianhydro-2-O-[4-[(3-chloro-2,4- B C C C A Cdifluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O- methyl-L-iditol59 1,4:3,6-dianhydro-2-O-[4-[(4,5-dichloro-2- B C C C A Cfluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-5-O- methyl-L-iditol60 1,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]- B C C B A B6-(methyloxy)quinazolin-7-yl]-5-O-(difluoromethyl)-L-iditol 611,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-fluorophenyl)amino]- B C C C A B6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 621,4:3,6-dianhydro-2-O-[4-[(3,4-dichlorophenyl)amino]-6- B C C C A B(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 631,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]- B C C D A B6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 641,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]- B C C B A B6-(methyloxy)quinazolin-7-yl]-5-O-ethyl-L-iditol 651,4:3,6-dianhydro-2-O-[4-[(3-bromo-2-methylphenyl)amino]- C C D D A C6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 661,4:3,6-dianhydro-2-O-[4-[(3-chloro-2-methylphenyl)amino]- C C D D A C6-(methyloxy)quinazolin-7-yl]-5-O-methyl-L-iditol 671,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]- C C C C A B6-(methyloxy)quinazolin-7-yl]-5-deoxy-D-xylo-hexitol 681,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]- C C C C A C6-(methyloxy)quinazolin-7-yl]-5-O-methyl-D-glucitol

TABLE 5 EphB4 Entry Name IC₅₀ 1N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(tetrahydro-2H-pyran-2- Aylmethyl)oxy]quinazolin-4-amine 2N-(3,4-dichlorophenyl)-7-[({5-[(dimethylamino)methyl]-1,2,4-oxadiazol- A3-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 3N-(3,4-dichlorophenyl)-7-[({3-[(dimethylamino)methyl]-1,2,4-oxadiazol- B5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 4N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(4-methylpiperazin-1- Byl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 5N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4- Aoxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 6N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-4-yl)- A1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 7N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(morpholin-4-ylmethyl)- B1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine 8N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(morpholin-2- Aylmethyl)oxy]quinazolin-4-amine 9N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-2-yl-1,2,4- Aoxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 10N-(3,4-dichlorophenyl)-7-[({2-[(dimethylamino)methyl]-1,3-thiazol-4- Byl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 11N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(phenylmethyl)morpholin-2- Byl]methyl}oxy)quinazolin-4-amine 12 1,1-dimethylethyl2-({[4-[(3,4-dichlorophenyl)amino]-6- B(methyloxy)quinazolin-7-yl]oxy}methyl)morpholine-4-carboxylate 13N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(morpholin-4-ylmethyl)-1,3-B thiazol-4-yl]methyl}oxy)quinazolin-4-amine 14N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4-methylpiperazin-1- Ayl)methyl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 15N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}-6- A(methyloxy)quinazolin-4-amine 16N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,4-oxazepan-2- Aylmethyl)oxy]quinazolin-4-amine 17N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-3-yl-1,2,4- Aoxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 18N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-2-yl)- A1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 19N-(3,4-dichlorophenyl)-7-{[(4-methyl-1,4-oxazepan-2-yl)methyl]oxy}-6- A(methyloxy)quinazolin-4-amine 20N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpiperidin-3-yl)- A1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine

TABLE 6 EphB4 EphA2 KDR Flt-1 EGFR ErbB2 Entry Name IC₅₀ IC₅₀ IC₅₀ IC₅₀IC₅₀ IC₅₀ 1 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(1,3-thiazol-4- B BB B A — ylmethyl)oxy]quinazolin-4-amine 2N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(pyridin-3- — B B B — —ylmethyl)oxy]quinazolin-4-amine 37-[(cyclopropylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- A B B — A B(methyloxy)quinazolin-4-amine 4N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(tetrahydrofuran-2- A B B — A —ylmethyl)oxy]quinazolin-4-amine 57-(cyclopentyloxy)-N-(3,4-dichlorophenyl)-6- B B C — A —(methyloxy)quinazolin-4-amine 6 methyl6-O-[4-[(3,4-dichlorophenyl)amino]-6- A B B — A B(methyloxy)quinazolin-7-yl]-alpha-D-glucopyranoside 7N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4-yl-2- C B C — A —oxoethyl)oxy]quinazolin-4-amine 8 1,1-dimethylethyl2-[3-({[4-[(3,4-dichlorophenyl)amino]-6- B C C — A —(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate 9 1,1-dimethylethyl4-[3-({[4-[(3,4-dichlorophenyl)amino]-6- B B B — A —(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate 10N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4-pyrrolidin-1- C C C — A —ylphenyl)-1,3-thiazol-2-yl]methyl}oxy)quinazolin-4-amine 11N-(3,4-dichlorophenyl)-7-[({4-[4-(diethylamino)phenyl]-1,3- C C C — A —thiazol-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 125-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- C C C —A — yl]oxy}methyl)-1,3-thiazol-4-yl]-2-hydroxybenzamide 137-[(2-cyclohexylethyl)oxy]-N-(3,4-dichlorophenyl)-6- C C C — A —(methyloxy)quinazolin-4-amine 147-[(cyclohexylmethyl)oxy]-N-(3,4-dichlorophenyl)-6- B C C — A —(methyloxy)quinazolin-4-amine 157-[(cyclobutylmethyl)oxy]-N-(3,4-dichlrophenyl)-6- B C C — A —(methyloxy)quinazolin-4-amine 16N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxolan-2-yl)ethyl]oxy}-6- B B B — A— (methyloxy)quinazolin-4-amine 17N-(3,4-dichlorophenyl)-7-{[2-(1,3-dioxan-2-yl)ethyl]oxy}-6- B B B — A —(methyloxy)quinazolin-4-amine 18N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-morpholin-4- B B B — A —ylethyl)oxy]quinazolin-4-amine 19N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-pyrrolidin-1- B B B — A —ylethyl)oxy]quinazolin-4-amine 20N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(2-piperidin-1- B B B — A —ylethyl)oxy]quinazolin-4-amine 212-(2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- A B B —A B yl]oxy}ethyl)-1H-isoindole-1,3(2H)-dione 22N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-3-yl-1,3- C C C — A— thiazol-2-yl)methyl]oxy}quinazolin-4-amine 23N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-2-yl-1,3- C C C — A— thiazol-2-yl)methyl]oxy}quinazolin-4-amine 24N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4-yl-1,3- C C C — A— thiazol-2-yl)methyl]oxy}quinazolin-4-amine 25N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-morpholin-4-yl-1,3- — C — AC thiazol-4-yl)methyl]oxy}quinazolin-4-amine 26N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-morpholin-4-yl- — C C — A —1,2,4-oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine 27N-(3,4-dichlorophenyl)-7-({[3-(dimethylamino)-1,2,4-oxadiazol-5- A C C —A — yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 28N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4-methylpiperazin- B B B —A — 1-yl)methyl]-1,3-thiazol-2-yl}methyl)oxy]quinazolin-4-amine 29N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7- B B B — A Btetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4- amine30 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(morpholin-4- B B B — A —ylmethyl)-1,3-thiazol-2-yl]methyl}oxy)quinazolin-4-amine 31N-(3,4-dichlorophenyl)-7-[({4-[(4-methyl-1,4-diazepan-1- A A A — A —yl)methyl]-1,3-thiazol-2-yl}methyl)oxy]-6-(methyloxy)quinazolin- 4-amine32 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5- B C B — A —{[(phenylmethyl)oxy]methyl}-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 33N-(3,4-dichlorophenyl)-7-{[(4-ethylmorpholin-2-yl)methyl]oxy}-6- A B A —A B (methyloxy)quinazolin-4-amine 34N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-4-yl-1,3- B B B —A A thiazol-4-yl)methyl]oxy}quinazolin-4-amine 35N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin- B B A —A B 4-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 361,1-dimethylethyl 4-[5-({[4-[(3,4-dichlorophenyl)amino]-6- C C C — A —(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate 37N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(3-piperazin-1-yl-1,2,4- B A A— A A oxadiazol-5-yl)methyl]oxy}quinazolin-4-amine 38N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[3-(4-methylpiperazin- B A A —A A 1-yl)-1,2,4-oxadiazol-5-yl]methyl}oxy)quinazolin-4-amine 39N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-2-yl)-1,2,4- A B A — A Aoxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 40N-(3,4-dichlorophenyl)-7-({[3-(4-ethylpiperazin-1-yl)-1,2,4- A A A — A —oxadiazol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 41N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[4- C C C — A —(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin- 4-amine42 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[4- C C C — B —(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4- amine43 7-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}oxy)-N-(3,4- C C C —B — dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 44N-(3,4-dichlorophenyl)-7-({[5-(3,5-dimethylisoxazol-4-yl)-1,2,4- C C C —A — oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 457-{[(5-chloro-1-benzothien-3-yl)methyl]oxy}-N-(3,4- C C C — B —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 46N-(3,4-dichlorophenyl)-7-[({3-[4-(1,1-dimethylethyl)phenyl]-1,2,4- C C C— B — oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 47N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({5-[2- C C C — A —(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}methyl)oxy]quinazolin- 4-amine48 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(4-methylphenyl)- C C C —A — 1,3,4-oxadiazol-2-yl]methyl}oxy)quinazolin-4-amine 49N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[1-(phenylmethyl)-1H- C C C — A— imidazol-2-yl]methyl}oxy)quinazolin-4-amine 50N-(3,4-dichlorophenyl)-7-({[3-(2,6-dichlorophenyl)-5- C C C — B —methylisoxazol-4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4- amine 51N-(3,4-dichlorophenyl)-7-{[(6-fluoro-4H-1,3-benzodioxin-8- C C C — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 527-{[(3,5-dibromophenyl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- C C C — B —(methyloxy)quinazolin-4-amine 53N-(3,4-dichlorophenyl)-7-{[(2,6-difluorophenyl)methyl]oxy}-6- B C C — A— (methyloxy)quinazolin-4-amine 54N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(pyridin-2- B B B — A —ylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4- amine55 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-phenyl-1,2,4- C C C — A —oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 567-({[4-chloro-2-(trifluoromethyl)quinolin-6-yl]methyl}oxy)-N-(3,4- C C C— B — dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 57N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(1-methylpyrrolidin-2- B B B— A — yl)ethyl]oxy}quinazolin-4-amine 58N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-4-yl)-1,2,4- A A A — A Aoxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 59N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpiperidin-3-yl)-1,2,4- A A A — A Aoxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 60N-(3,4-dichlorophenyl)-7-({[2-(dimethylamino)-1,3-thiazol-4- C C C — A —yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 61N-(3,4-dichlorophenyl)-7-{[(4-ethyl-1,4-oxazepan-2- A A A — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 62N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-4-yl)-1,3-thiazol- A B A— A — 4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 63N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-pyrrolidin-2-yl]- A BB — A — 1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 64N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-pyrrolidin-2-yl]- B BB — A — 1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 65[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- C C C — A— yl]oxy}methyl)-1,3-thiazol-2-yl]methyl benzoate 66[4-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- B C B — A— yl]oxy}methyl)-1,3-thiazol-2-yl]methanol 67N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-methyl-4,5,6,7- A B B — A Atetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}quinazolin-4-amine 68N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(4S)-1,3-thiazolidin- B B B— A — 4-yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4-amine 69N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-2-yl-1,3- A A A —A A thiazol-4-yl)methyl]oxy}quinazolin-4-amine 70N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin- B B A —A — 2-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 71N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperidin-3-yl-1,3- B B B —A thiazol-4-yl)methyl]oxy}quinazolin-4-amine 72N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(1-methylpiperidin- B B B —A B 3-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 73N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-2-yl)-1,3-thiazol- B B A— A — 4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 74N-(3,4-dichlorophenyl)-7-({[2-(1-ethylpiperidin-3-yl)-1,3-thiazol- B C B— A — 4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 75N-(3,4-dichlorophenyl)-7-[({3-[(2S)-1-ethylpyrrolidin-2-yl]-1,2,4- A B B— A — oxadiazol-5-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 76N-(3,4-dichlorophenyl)-7-[({2-[(2S)-1-ethylpyrrolidin-2-yl]-1,3- B B B —A — thiazol-4-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 77N-(3,4-dichlorophenyl)-7-{[(5-ethyl-4,5,6,7- A B B — A Atetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 78N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propyl-1,4- A A A — B Boxazepan-2-yl)methyl]oxy}quinazolin-4-amine 797-({[4-(cyclopropylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-N- A A A — A —(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 80N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2-(methyloxy)ethyl]- A B B— A — 1,4-oxazepan-2-yl}methyl)oxy]quinazolin-4-amine 81N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)-1,4-oxazepan-2- B B B — A— yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 82N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(2-piperazin-1-yl-1,3- B B B —A — thiazol-4-yl)methyl]oxy}quinazolin-4-amine 83N-(3,4-dichorophenyl)-6-(methyloxy)-7-{[(5-pyrroidin-2-yl-1,2,4- B B B —A — oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine 84N-(3,4-dichlorophenyl)-7-({[5-(1-ethylpyrrolidin-2-yl)-1,2,4- A B B — A— oxadiazol-3-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 85N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({3-[(2S)-1- B B B — A —methylpyrrolidin-2-yl]-1,2,4-oxadiazol-5-yl}methyl)oxy]quinazolin-4-amine 86N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({2-[(2S)-1- B B B — A —methylpyrrolidin-2-yl]-1,3-thiazol-4-yl}methyl)oxy]quinazolin-4- amine87 N-(3,4-dichlorophenyl)-7-({[2-(4-ethylpiperazin-1-yl)-1,3-thiazol- BB A — A — 4-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 88N-(3,4-dichlorophenyl)-7-{[(1,4-dimethylpiperazin-2- B B C — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 897-{[(4-cyclopentylmorpholin-2-yl)methyl]oxy}-N-(3,4- B A A — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 90N-(3,4-dichlorophenyl)-7-({[4-(1-methylethyl)morpholin-2- B B A — A —yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 91N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3- B B B — A —phenylpropyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 92N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[2- A B B — A —(methyloxy)ethyl]morpholin-2-yl}methyl)oxy]quinazolin-4-amine 93 ethyl2-[2-({[4-[(3,4-dichlorophenyl)amino]-6- B B B — A —(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4- yl]propanoate 94N-(3,4-dichlorophenyl)-7-{[(4-hex-5-en-1-ylmorpholin-2- A A A — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 952-({2-[2-({[4-[(3,4-dichlorophenyl)amino]-6- B B B — A —(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4- yl]ethyl}oxy)ethanol96 methyl 3-[2-({[4-[(3,4-dichlorophenyl)amino]-6- A A A — A —(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4- yl]propanoate 976-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- A B A —A B yl]oxy}methyl)morpholin-4-yl]hexanenitrile 98N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H- A A A — A —pyran-2-ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 994-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- A A A —A — yl]oxy}methyl)morpholin-4-yl]butanenitrile 100N-(3,4-dichlorophenyl)-7-[({4-[(4-fluorophenyl)methyl]morpholin- B B B —A — 2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 101 methyl5-[2-({[4-[(3,4-dichlorophenyl)amino]-6- B B B — A —(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4- yl]pentanoate 102N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-oct-7-en-1- B B B — A —ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 103N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propylmorpholin-2- A B B — A— yl)methyl]oxy}quinazolin-4-amine 1046-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- A B A —A — yl]oxy}methyl)morpholin-4-yl]hexan-1-ol 1057-{[(4-acetylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)- A B B —A — 6-(methyloxy)quinazolin-4-amine 1067-({[4-(cyclopropylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4- A A A — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 107N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-yn-1- A A A — A —ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 108N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pyridin-4- A A A — A —ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 109N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(pyridin-2- B B A — A —ylmethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 110N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-2-yn-1- B B B — A —ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 111N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(4-methylpiperazin- B B B —A B 1-yl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 112N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[5-(1-methylpyrrolidin- B B B —A — 2-yl)-1,2,4-oxadiazol-3-yl]methyl}oxy)quinazolin-4-amine 113N-(3-chloro-4-fluorophenyl)-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 1147-{[(4-acetyl-1-ethylpiperazin-2-yl)methyl]oxy}-N-(3,4- A B C — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 115N-[4-chloro-2,5-bis(methyloxy)phenyl]-7-{[(4-methylmorpholin-2- B B C —B — yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 116N-(3-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 1177-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(3,4,5- A B B —A B trichlorophenyl)quinazolin-4-amine 118N-(3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2- A A B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 119N-(3,4-dichlorophenyl)-7-{[(4-ethanimidoyl-1,4-oxazepan-2- A A A — A Ayl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 120N-(4-bromo-2-fluorophenyl)-7-{[(4-methylmorpholin-2- B B A — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 121N-(5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 122N-(4-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- B B A — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 123N-(2,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}- B B B —A — 6-(methyloxy)quinazolin-4-amine 124N-(2,4-dibromophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}- B B B — A— 6-(methyloxy)quinazolin-4-amine 1257-{[(4-methylmorpholin-2-yl)methyl]oxy}-6-(methyloxy)-N-(2,3,4- A A A —A B trichlorophenyl)quinazolin-4-amine 126N-(3,4-dichlorophenyl)-7-{[(1-ethyl-4-methylpiperazin-2- B B C — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 127N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6- A A A — A A(methyloxy)quinazolin-7-yl]oxy}methyl)morpholine-4- carboximidamide 128N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[2-(pyrrolidin-1- B B B — A —ylmethyl)-1,3-thiazol-4-yl]methyl}oxy)quinazolin-4-amine 129N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(tetrahydro-2H- A B B — A —pyran-4-yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 130N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)morpholin-2- B B B — A —yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 1317-({[4-(cyclohexylmethyl)morpholin-2-yl]methyl}oxy)-N-(3,4- B B B — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1322-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- B B B —A — yl]oxy}methyl)morpholin-4-yl]ethanol 1337-{[(4-but-2-yn-1-ylmorpholin-2-yl)methyl]oxy}-N-(3,4- B B B — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1347-{[(4-cyclobutylmorpholin-2-yl)methyl]oxy}-N-(3,4- B B A — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 135N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxolan-2- A B B — A —yl)ethyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4- amine 1367-({[4-(2-cyclohexylethyl)morpholin-2-yl]methyl}oxy)-N-(3,4- B B B — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 137N-(3,4-dichlorophenyl)-7-[({4-[2-(1,3-dioxan-2- A B B — A —yl)ethyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4- amine 138N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pent-4-en-1- A B A — A —ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 139N-(3,4-dichlorophenyl)-7-[({4-[(2R)-2-methylbutyl]morpholin-2- B B B — A— yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 140N-(3,4-dichlorophenyl)-7-({[4-(4-fluorobutyl)morpholin-2- A B A — A —yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 1413-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- B B B —A — yl]oxy}methyl)morpholin-4-yl]butan-2-one 1421-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- B B B —A — yl]oxy}methyl)morpholin-4-yl]butan-2-one 143N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-pentylmorpholin-2- B B B — A— yl)methyl]oxy}quinazolin-4-amine 144N-(3,4-dichlorophenyl)-7-{[(4-hexylmorpholin-2-yl)methyl]oxy}-6- B B B —A — (methyloxy)quinazolin-4-amine 145N-(3,4-dichlorophenyl)-7-{[(4-heptylmorpholin-2-yl)methyl]oxy}- B C B —A — 6-(methyloxy)quinazolin-4-amine 146N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-octylmorpholin-2- B C C — A— yl)methyl]oxy}quinazolin-4-amine 147N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2- B C B — A —phenylethyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 1487-{[(4-butylmorpholin-2-yl)methyl]oxy}-N-(3,4-dichlorophenyl)-6- A B A —A B (methyloxy)quinazolin-4-amine 149N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-prop-2-en-1- B B B — A —ylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 1502-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- B B B —A — yl]oxy}methyl)morpholin-4-yl]-1-phenylethanone 151N-(3,4-dichlorophenyl)-7-({[4-(2-fluoroethyl)morpholin-2- B B B — A —yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 152N-(3,4-dichlorophenyl)-7-({[4-(3-methylbut-2-en-1-yl)morpholin- B B B —A — 2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 1537-[({4-[(2E)-3-bromoprop-2-en-1-yl]morpholin-2-yl}methyl)oxy]- B B B — A— N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1542-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- A B B —A A yl]oxy}methyl)morpholin-4-yl]acetamide 155N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[3-(tetrahydro-2H- A B A — A— pyran-2-yloxy)propyl]-1,4-oxazepan-2-yl}methyl)oxy]quinazolin- 4-amine156 N-(3,4-dichlorophenyl)-7-({[4-(3-methylbutyl)-1,4-oxazepan-2- B B B— A — yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 1577-({[4-(cyclohexylmethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4- B B A —A — dichlorophenyl)methyl]-6-(methyloxy)quinazoline 1587-({[4-(2-cyclohexylethyl)-1,4-oxazepan-2-yl]methyl}oxy)-4-[(3,4- B B B— A — dichlorophenyl)methyl]-6-(methyloxy)quinazoline 159N-(3,4-dichlorophenyl)-7-({[4-(2-ethylbutyl)-1,4-oxazepan-2- B B B — A —yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 160N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(methylsulfonyl)-1,4- A B B— A A oxazepan-2-yl]methyl}oxy)quinazolin-4-amine 161N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(1-methylpiperidin- A B A —A — 4-yl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 162N-(3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 163N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6- A B B — A A(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-oxazepane-4- carboximidamide164 N-(3-bromo-4-methylphenyl)-7-{[(4-methylmorpholin-2- A B A — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 165N-(3,4-dichlorophenyl)-7-{[(1,4-diethylpiperazin-2-yl)methyl]oxy}- B B C— A — 6-(methyloxy)quinazolin-4-amine 1664-({[4-[(4-bromo-2-fluorophenyl)amino]-6-(methyloxy)quinazolin- B B A —A — 7-yl]oxy}methyl)-N′-cyanopiperidine-1-carboximidamide 167N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4- A A B — A A(methylsulfonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 168N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4- B B B — A —[(phenylmethyl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4- amine169 N-(3,4-dichlorophenyl)-7-[({4-[(4- B C B — A —fluorophenyl)sulfonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 170N-(3,4-dichlorophenyl)-7-({[4-(ethylsulfonyl)morpholin-2- A A B — A Ayl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 171N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4- B C B — A —(phenylsulfonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 1727-[({4-[(3-chloropropyl)sulfonyl]morpholin-2-yl}methyl)oxy]-N- A B B — AB (3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1737-({[4-(butylsulfonyl)morpholin-2-yl]methyl}oxy)-N-(3,4- B B B — A —dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 174N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(4- C C B — A —methylphenyl)sulfonyl]morpholin-2-yl}methyl)oxy]quinazolin-4- amine 175N-(3,4-dichlorophenyl)-7-[({4-[(3,5-dimethylisoxazol-4- A B B — A Ayl)carbonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin- 4-amine176 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-{[3- B B B — A —(methyloxy)phenyl]acetyl}morpholin-2-yl)methyl]oxy}quinazolin- 4-amine177 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2- B B B — A —methylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 1787-[({4-[(4-butylphenyl)carbonyl]morpholin-2-yl}methyl)oxy]-N- C C C — A— (3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1797-[({4-[(4-chlorophenyl)acetyl]morpholin-2-yl}methyl)oxy]-N-(3,4- B C B— A — dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 180N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2- B B B — A —propylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 181N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(4- B B B — A —methylpentanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 182N-(3,4-dichlorophenyl)-7-[({4-[(2,5- B B B — A —difluorophenyl)carbonyl]morpholin-2-yl}methyl)oxy]-6-(methyloxy)quinazolin-4-amine 1837-({[4-(cyclopentylcarbonyl)morpholin-2-yl]methyl}oxy)-N-(3,4- A B B — AA dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 184N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(2- B C B — A —phenylbutanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 185N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[({4-[(2,3,6- B B B — A —trifluorophenyl)carbonyl]morpholin-2-yl}methyl)oxy]quinazolin-4- amine186 N-(3,4-dichlorophenyl)-7-({[4-(furan-3-ylcarbonyl)morpholin-2- A B B— A — yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 187N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4-propanoylmorpholin- A B B —A A 2-yl)methyl]oxy}quinazolin-4-amine 188N-(3,4-dichlorophenyl)-7-{[(4-hexanoylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 189N-(3,4-dichlorophenyl)-7-({[4-(2-ethylhexanoyl)morpholin-2- B B B — A —yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 190N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(3- B B B — A —phenylpropanoyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 191N-(3,4-dichlorophenyl)-7-({[4-(2,2-dimethylpropanoyl)morpholin- B B B —A — 2-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine 192N-(3,4-dichlorophenyl)-6-(methyloxy)-7-({[4-(naphthalen-1- B C B — A —ylcarbonyl)morpholin-2-yl]methyl}oxy)quinazolin-4-amine 1937-[({4-[(2-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]- A B A— A A N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1947-[({4-[(6-chloropyridin-3-yl)carbonyl]morpholin-2-yl}methyl)oxy]- A B B— A — N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 1957-({[4-(1,3-benzodioxol-5-ylcarbonyl)morpholin-2-yl]methyl}oxy)- B B B —A — N-(3,4-dichlorophenyl)-6-(methyloxy)quinazolin-4-amine 196N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-[(morpholin-2- A A A — AA ylmethyl)oxy]quinazolin-4-amine 197N-(3,4-dichlorophenyl)-6-{[2-(methyloxy)ethyl]oxy}-7- A B A — A —[(morpholin-2-ylmethyl)oxy]quinazolin-4-amine 198N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-[(morpholin-2- A A A — A Aylmethyl)oxy]quinazolin-4-amine 199N-(3,4-dichlorophenyl)-6-(ethyloxy)-7-{[(4-methylmorpholin-2- A A A — AA yl)methyl]oxy}quinazolin-4-amine 200N-(4-bromo-2-methylphenyl)-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 201N-(4-chloro-3-methylphenyl)-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 202N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6- A B B — A A(methyloxy)quinazolin-7-yl]oxy}methyl)-N-methylmorpholine-4-carboximidamide 203 N-(4-bromo-3-chlorophenyl)-7-{[(4-methylmorpholin-2-A A A — A B yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 204N-(3,4-dichlorophenyl)-6-[(1-methylethyl)oxy]-7-{[(4- A A A — A Amethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 205N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-2-yl)methyl]oxy}- A B B —A — 6-{[2-(methyloxy)ethyl]oxy}quinazolin-4-amine 206N-(4-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 2077-{[(4-acetyl-1,4-oxazepan-2-yl)methyl]oxy}-N-(3,4- A B B — A Adichlorophenyl)-6-(methyloxy)quinazolin-4-amine 2084-[(3,4-dichlorophenyl)amino]-7-{[(4-methylmorpholin-2- B B B — A —yl)methyl]oxy}quinazolin-6-ol 209N-(3-bromo-4-chlorophenyl)-7-{[(4-methylmorpholin-2- A B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 2103-[2-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- A A A —A — yl]oxy}methyl)morpholin-4-yl]-3-oxopropanoic acid 211 methyl4-[2-({[4-[(3,4-dichlorophenyl)amino]-6- B B B — A —(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl]-4- oxobutanoate212 N-(3,4-dichlorophenyl)-7-{[(4-methylmorpholin-3-yl)methyl]oxy}- B BC — A — 6-(methyloxy)quinazolin-4-amine 213N-(3-bromo-2-chlorophenyl)-7-{[(4-methylmorpholin-2- A B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 214N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6- A B B — A —(methyloxy)quinazolin-7-yl]oxy}methyl)-N-[2-(methyloxy)ethyl]morpholine-4-carboximidamide 215N′-cyano-2-({[4-[(3,4-dichlorophenyl)amino]-6- A B B — A A(methyloxy)quinazolin-7-yl]oxy}methyl)-N-ethylmorpholine-4-carboximidamide 216 [(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6- A B B —A A (methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](piperidin-1-yl)methylidene]cyanamide 217[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6- A A B — A A(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](pyrrolidin-1-yl)methylidene]cyanamide 218[(1E)-[2-({[4-[(3,4-dichlorophenyl)amino]-6- A B A — A —(methyloxy)quinazolin-7-yl]oxy}methyl)morpholin-4-yl](4-methylpiperazin-1-yl)methylidene]cyanamide 219N-(3,4-dichlorophenyl)-7-{[(6-ethyl-4,6-dimethylmorpholin-2- B B B — A —yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 220N-(4-bromo-3-methylphenyl)-7-{[(4-methylmorpholin-2- B B B — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 221N-(3,4-dichlorophenyl)-7-{[(6,6-dimethylmorpholin-2- B A — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 222N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,6,6- B B — A Btrimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 223N-(3,4-dichlorophenyl)-7-{[2-(5,5-dimethylmorpholin-2- B B B — A Byl)ethyl]oxy}-6-(methyloxy)quinazolin-4-amine 224N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,5,5- B B B — A Btrimethylmorpholin-2-yl)ethyl]oxy}quinazolin-4-amine 2251,1-dimethylethyl 2-(2-{[4-[(3,4-dichlorophenyl)amino]-6- C C C — A C(methyloxy)quinazolin-7-yl]oxy}ethyl)-5,5-dimethylmorpholine-4-carboxylate 226 N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5- A B A —A A trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 227N-(4-bromo-2,3-dichlorophenyl)-7-{[(4-methylmorpholin-2- A B B — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 228N-(4,5-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- A B B — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 229N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[2-(4,6,6- B C B — A Btrimethylmorpholin-2-yl)ethyl]oxy}quinazolin-4-amine 230N-(4-bromo-2,3-difluorophenyl)-7-{[(4-methylmorpholin-2- B B A — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 231N-(4-bromo-2,5-difluorophenyl)-7-{[(4-methylmorpholin-2- B B A — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 232N-(4-bromo-3,5-difluorophenyl)-7-{[(4-methylmorpholin-2- B B A — A Byl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 233N-(3,4-dichloro-2-methylphenyl)-7-{[(4-methylmorpholin-2- A B B — A Cyl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 234N-(4-bromo-3-chloro-2-methylphenyl)-7-{[(4-methylmorpholin-2- B B B — AB yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 235N-(4-bromo-5-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- A B A — AB yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 236N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- A A A — AA yl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 237N-(3,4-dichloro-2-fluorophenyl)-7-{[(4-methylmorpholin-2- A A A — A Ayl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 238N-(3-chloro-2,4-difluorophenyl)-7-{[(4-methylmorpholin-2- A A A — A Ayl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 239N-(2,3-dichloro-4-methylphenyl)-7-{[(4-methylmorpholin-2- B B A — A Cyl)methyl]oxy}-6-(methyloxy)quinazolin-4-amine 2406-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7- A B B — AB yl]oxy}methyl)-3,3,4-trimethylmorpholin-2-one 241N-(4-bromo-2,3-dichlorophenyl)-6-(methyloxy)-7-{[(4,5,5- A A B — A Btrimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 242N-(4-bromo-5-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- A A A — AB trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 243N-(4,5-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- A A A — A Atrimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 244N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- A A A — A Atrimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 245N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(4,5,5- A A A — AA trimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 246N-(3-chloro-2,4-difluorophenyl)-6-(methyloxy)-7-{[(4,5,5- A A B — A Btrimethylmorpholin-2-yl)methyl]oxy}quinazolin-4-amine 247(6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- B B B — A B(methyloxy)quinazolin-7-yl]oxy}methyl)-4-methylpiperazin-2-one 248(6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- B B B — A B(methyloxy)quinazolin-7-yl]oxy}methyl)-4-methylpiperazin-2-one 249(6S)-6-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6- B B B — A C(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-dimethylpiperazin-2- one 250(6S)-6-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6- B B B — A C(methyloxy)quinazolin-7-yl]oxy}methyl)-1,4-dimethylpiperazin-2- one 251N-(4-bromo-3-chlorophenyl)-7-{[(3a′S,4R,6′S,6a′R)-2,2- B C C — A Cdimethyltetrahydrospiro[1,3-dioxolane-4,3′-furo[3,2-b]furan]-6′-yl]oxy}-6-(methyloxy)quinazolin-4-amine 2531,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- C C C — A C(methyloxy)quinazolin-7-yl]-5-O-(methylsulfonyl)-D-glucitol 2541,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A B(methyloxy)quinazolin-7-yl]-D-glucitol 2551,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A C(methyloxy)quinazolin-7-yl]-5-S-methyl-5-thio-L-iditol 2561,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A C(methyloxy)quinazolin-7-yl]-2-deoxy-2-morpholin-4-yl-L-iditol 2571,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A C(methyloxy)quinazolin-7-yl]-2-deoxy-2-(4-methylpiperazin-1-yl)- L-iditol258 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C —A C (methyloxy)quinazolin-7-yl]-2-deoxy-2-pyrrolidin-1-yl-L-iditol 2592-O-acetyl-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3- B C C — A Cchlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-L-iditol 2601,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A B(methyloxy)quinazolin-7-yl]-L-iditol 2611,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A B(methyloxy)quinazolin-7-yl]-2-deoxy-2-(methylsulfonyl)-L-iditol 2622-amino-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3- B C C — A Cchlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-L- iditol 2631,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A C(methyloxy)quinazolin-7-yl]-2-deoxy-2-(dimethylamino)-L-iditol 2641,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C B — A C(methyloxy)quinazolin-7-yl]-2-deoxy-2-(diethylamino)-L-iditol 2651,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A C(methyloxy)quinazolin-7-yl]-2-deoxy-2-piperidin-1-yl-L-iditol 2662-(acetylamino)-1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3- B C C — A Cchlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]-2-deoxy-L- iditol 2671,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- C C C — A B(methyloxy)quinazolin-7-yl]-5-O-methyl-5-C-(trifluoromethyl)-D- glucitol268 1,4:3,6-dianhydro-5-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C —A B (methyloxy)quinazolin-7-yl]-2-deoxy-2-[(methylsulfonyl)amino]-L-iditol 269 N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(1- B C B — A Cmethylpyrrolidin-3-yl)oxy]quinazolin-4-amine 270N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-[(3R)- B C B — A Btetrahydrofuran-3-yloxy]quinazolin-4-amine 2711,4:3,6-dianhydro-5-O-[4-[(3-chloro-2-fluorophenyl)amino]-6- B C C — A B(methyloxy)quinazolin-7-yl]-2-deoxy-2-fluoro-L-iditol 272N-(4-bromo-3-chlorophenyl)-6-(methyloxy)-7-{[(3S,4R)-4- B C C — A B(methyloxy)tetrahydrofuran-3-yl]oxy}quinazolin-4-amine 2731,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-(6-(methyloxy)-4-{[4-(4- C C C —A C methylpiperazin-1-yl)phenyl]amino}quinazolin-7-yl)-L-iditol 2741,4:3,6-dianhydro-2-deoxy-2-fluoro-5-O-[4-{[3-fluoro-4-(4- C C C — A Cmethylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-L-iditol 275 1,4:3,6-dianhydro-2-deoxy-5-O-[4-{[2,3-dichloro-4-(4- CC C — A C methylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-L-iditol 2761,4:3,6-dianhydro-2-deoxy-5-O-[4-{[3,4-dichloro-2-(4- C C C — A Cmethylpiperazin-1-yl)phenyl]amino}-6-(methyloxy)quinazolin-7-yl]-2-fluoro-L-iditol 2771,4:3,6-dianhydro-2-O-[4-[(4-bromo-3-chlorophenyl)amino]-6- B C C — A B(methyloxy)quinazolin-7-yl]-5-C-(trifluoromethyl)-D-glucitol

1. A solid dosage formulation comprising a therapeutically effectiveamount of a compound of Formula I,

or a single stereoisomer, racemate, enantiomer, or diastereomer, thereofand optionally as a pharmaceutically acceptable salt thereof, togetherwith one or more materials selected from excipients (or carriers),fillers, extenders, binders, humectants, disintegrating agents, solutionretarders, absorption accelerators, wetting agents, adsorbents,lubricants, and buffering agents, wherein the solid dosage form is apill, tablet, or capsule, and wherein, R¹ is methyl; R² is selected fromhalogen, trihalomethyl, —CN, —NH₂, —NO₂, —OR³, —N(R³)R⁴, —S(O)O₂R⁴,—SO₂N(R³)R⁴, —CO₂R³, —C(═O)N(R³)R⁴, —N(R³)SO₂R⁴, —N(R³)C(═O)R³,—N(R³)CO₂R⁴, —C(═O)R³, lower alkyl, lower alkenyl, and lower alkynyl; R³is —H or R⁴; R⁴ is selected from lower alkyl; lower alkyl substitutedwith one, two, or three halogen; aryl; aryl substituted with one, two,or three halogen; and unsubstituted lower arylalkyl; or R³ and R⁴, whentaken together with a common nitrogen to which they are attached, formmorpholinyl, pyrrolidinyl, piperidinyl. or piperazinyl optionallysubstituted by one, two, or three alkyl; q is 0, 1, 2, 3, 4, or 5; Z is—NR—; R⁵ is —H; M₁-M₂-M₃-M₄-together are according to formula II:

wherein X¹, X², and optionally X³, represent the atoms of a saturatedbridged ring system, said saturated bridged ring system containing up tothree annular heteroatoms represented by any of X¹, X², and X³; wherein,each X¹ is independently selected from —C(R⁶)R⁷—, —O—, —S(O)₀₋₂—, and—NR⁸—; each X² is independently a bridgehead methine optionallysubstituted with R⁶, or a bridgehead nitrogen; each X³ is independentlyselected from —C(R⁶)R⁷, —O—, —S(O)₀₋₂—, and —NR⁸—; provided, for X¹, X²,and X³, there are no nitrogen-nitrogen annular bonds nor geminaldi-nitrogen substitutions; E is absent; Y is —CH₂— provided that Y isnot directly attached to any heteroatom represented by X¹, X² or X³; mand p are each independently 1, 2, 3, or 4; n is 0, 1, or 2, when n iszero, then there is a direct single bond between the two bridgeheadX²'s; R⁶ and R⁷ are each independently selected from —H, halogen,trihalomethyl, —CN, —NH₂, —NO₂, —OR³, —N(R³)R⁴, —S(O)o-₂R⁴, —SO₂N(R³)R⁴,—CO₂R³, —C(O)N(R³)R⁴, —N(R³)SO₂R⁴, —N(R³)C(O)R³, —NCO₂R³, —C(O)R³, loweralkyl, aryl, and unsubstituted lower arylalkyl; or R⁶ and R⁷, when takentogether are oxo; or R⁶ and R⁷, when taken together with a common carbonto which they are attached, form a three- to seven-membered spirocyclyloptionally containing at least one additional heteroatom selected fromN, O, S, and P and wherein the spirocyclic ring is optionallysubstituted with one or two alkyl; and R⁸ is selected from R³,—SO₂N(R³)R⁴, —CO₂R³, —C(O)N(R³)R⁴, —SO₂R⁴, and —C(O)R³; with the provisothat when Y is a C₁₋₃ alkylene linker, E is absent, Z is —NH— or—N(CH₃)—, R¹ is a C₁₋₃ alkyl, R² is —H or halogen, n=O, and the atoms X¹of one bridge of the saturated bridged ring system, when combined withboth bridgehead atoms, X², of the saturated bridged ring system,represent: either a pyrrolidine ring or a piperidine ring, and any atom,X¹ or X², of either of said pyrrolidine ring or said piperidine ring isattached to Y; then the other bridge of said saturated bridged ringsystem cannot be any one of —OC(O)CH₂—, —CH₂OC(O)—, —OC(O)CH₂CH₂—,—CH₂OC(O)CH₂—, —CH₂CH₂OC(O)—, —OC(O)CH₂NH—, —OC(O)CH₂N(C₁₄alkyl)-, and—OC(O)CH₂O—; and either a piperazine ring or a 4-(C₁₋₄ alkyl)-piperazinering, and any atom, X¹ or X², of either of said piperazine ring or said4-(C₁₋₄ alkyl)-piperazine ring is attached to Y; then the other bridgeof said saturated bridged ring system, only when attached via the 2- andthe 3-position of either of said piperazine ring or said 4-(C₁₋₄alkyl)-piperazine ring, cannot be one of —CH₂OC(O)CH₂—, —CH₂CH₂OC(O)—,and either of the two aforementioned bridges substituted by one or twoC₁₋alkyl groups; and a piperazine ring, and any atom, X¹ or X², of saidpiperazine ring is attached to Y; then the other bridge of saidsaturated bridged ring system, only when attached via the 3- and the4-position of said piperazine ring, cannot be —C(O)OCH₂CH₂—,—CH₂OC(O)CH₂—, —C(O)OCH₂CH₂— substituted with one or two C₁₋₂ alkylgroups, or —CH₂OC(O)CH₂— substituted with one or two C₁₋₂ alkyl groups(but only when the four above mentioned bridges are attached to the₃-position of said piperazine ring via their left-hand end as depictedabove); and a 2-oxomorpholine ring, said 2-oxomorpholine ring attachedto Y via its 4-position; then the other bridge of said saturated bridgedring system, only when attached via the 5- and the 6-position of said2-oxomorpholine ring, cannot be one of —(CH₂)_(g)—, —CH₂WCH₂—,—CH₂WCH₂CH₂—, and —CH₂CH₂WCH₂, wherein W is —O—, —S(O)₀₋₂—, —NH—, or—N(C₁₋₄ alkyl)- and wherein g is 2, 3, or
 4. 2. The solid dosage formaccording to claim 1, wherein R² is selected from halogen,trihalomethyl, —CN, —NO₂, —OR³, and lower alkyl; or a singlestereoisomer, racemate, enantiomer, or diastereomer, thereof andoptionally as a pharmaceutically acceptable salt thereof.
 3. The soliddosage form according to claim 2, wherein the saturated bridged ringsystem has a geometry selected from the group consisting of [4.4.0],[4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2],[3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1]; or a singlestereoisomer, racemate, enantiomer, or diastereomer, thereof andoptionally as a pharmaceutically acceptable salt thereof.
 4. The soliddosage form according to claim 3, wherein q is 1, 2, or 3; or a singlestereoisomer, racemate, enantiomer, or diastereomer, thereof andoptionally as a pharmaceutically acceptable salt thereof.
 5. The soliddosage form according to claim 4, wherein the saturated bridged ringsystem has a geometry selected from the group consisting of [4.4.0],[4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0]; or a singlestereoisomer, racemate, enantiomer, or diastereomer, thereof andoptionally as a pharmaceutically acceptable salt thereof.
 6. The soliddosage form according to claim 5, wherein said saturated bridged ringsystem contains one or two annular nitrogens, said one or two annularnitrogens are selected from —NR⁸—, when X¹, and a bridgehead nitrogen,when X²; or a single stereoisomer, racemate, enantiomer, ordiastereomer, thereof and optionally as a pharmaceutically acceptablesalt thereof.
 7. The solid dosage form according to claim 6, whereinsaid saturated bridged ring system is according to either formula V orformula VI,

wherein R⁸ is selected from —H, lower alkyl, —COR³, —C(O)N(R³)R⁴,—SO₂R⁴, and —C(O)R³; or a single stereoisomer, racemate, enantiomer, ordiastereomer, thereof and optionally as a pharmaceutically acceptablesalt thereof.
 8. The solid dosage form according to claim 7, wherein

of I is selected from

wherein R^(2a), R^(2b), and R^(2c) are each independently selected fromF, Cl, and Br; or a single stereoisomer, racemate, enantiomer, ordiastereomer, thereof and optionally as a pharmaceutically acceptablesalt thereof.
 9. The solid dosage form according to claim 8, whereinR^(2a) is F, R^(2b) is Cl, and R^(2c) is either Cl or Br; or a singlestereoisomer, racemate, enantiomer, or diastereomer, thereof andoptionally as a pharmaceutically acceptable salt thereof.
 10. The soliddosage form according to claim 9, wherein R⁸ is methyl or ethyl; or asingle stereoisomer, racemate, enantiomer, or diastereomer, thereof andoptionally as a pharmaceutically acceptable salt thereof.
 11. The soliddosage form of claim 1 wherein the compound isN-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amineoptionally as a pharmaceutically acceptable salt thereof.
 12. A methodof inhibiting a receptor tyrosine kinase in a cell in a human, whereinthe receptor tyrosine kinase is selected from the group consisting ofkinase insert domain receipt, epidermal growth factor receptor, andErbB2, the method comprising administering to the human a solid dosageformulation according to claim
 1. 13. A method of inhibiting a receptortyrosine kinase in a cell in a human, wherein the receptor tyrosinekinase is selected from the group consisting of kinase insert domainreceipt, epidermal growth factor receptor, and ErbB2, the methodcomprising administering to the human a solid dosage formulationaccording to claim
 3. 14. A method of inhibiting a receptor tyrosinekinase in a cell in a human, wherein the receptor tyrosine kinase isselected from the group consisting of kinase insert domain receipt,epidermal growth factor receptor, and ErbB2, the method comprisingadministering to the human a solid dosage formulation according to claim7.
 15. A method of inhibiting a receptor tyrosine kinase in a cell in ahuman, wherein the receptor tyrosine kinase is selected from the groupconsisting of kinase insert domain receipt, epidermal growth factorreceptor, and ErbB2, the method comprising administering to the human asolid dosage formulation according to claim
 11. 16. The method of claim12, wherein the receptor tyrosine kinase is kinase insert domainreceptor.
 17. The method of claim 12, wherein the receptor tyrosinekinase is epidermal growth factor receptor.
 18. The method of claim 12,wherein the receptor tyrosine kinase is ErbB2.
 19. The method of claim15, wherein the receptor tyrosine kinase is kinase insert domainreceptor.
 20. The method of claim 15, wherein the receptor tyrosinekinase is epidermal growth factor receptor.
 21. The method of claim 15,wherein the receptor tyrosine kinase is ErbB2.